Fluorinated 4-azasteroid derivatives as androgen receptor modulators

ABSTRACT

Compounds of structural formula I are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

This application is a continuation of U.S. Ser. No. 11/605,090, filedNov. 28, 2006 now abandoned which is a continuation of U.S. Ser. No.10/507,239 filed Sep. 9, 2004 (which issued on Mar. 6, 2007 as U.S. Pat.No. 7,186,838), which is a U.S. National Phase application under 35U.S.C. 371 of PCT Application number PCT/US03/08277, filed Mar. 7, 2003.

FIELD OF THE INVENTION

The present invention relates to fluorinated 4-azasteroid derivatives,their synthesis, and their use as androgen receptor modulators. Moreparticularly, the compounds of the present invention aretissue-selective androgen receptor modulators and are thereby useful forthe treatment of conditions caused by androgen deficiency or which canbe ameliorated by androgen administration, such as osteoporosis,periodontal disease, bone fracture, frailty, and sarcopenia.

BACKGROUND OF THE INVENTION

The androgen receptor (AR) belongs to the superfamily of steroid/thyroidhormone nuclear receptors, whose other members include the estrogenreceptor (ER), the progesterone receptor (PR), the glucocorticoidreceptor (GR), and the mineralocorticoid receptor (MR). The AR isexpressed in numerous tissues of the body and is the receptor throughwhich the physiological as well as the pathophysiological effects ofendogenous androgen ligands, such as testosterone (T) anddihydrotestosterone (DHT), are expressed. Structurally, the AR iscomposed of three main functional domains: the ligand binding domain(LBD), the DNA-binding domain, and amino-terminal domain. A compoundthat binds to the AR and mimics the effects of an endogenous AR ligandis referred to as an AR agonist, whereas a compound that inhibits theeffects of an endogenous AR ligand is termed an AR antagonist.

Androgen ligand binding to the AR affords a ligand/receptor complex,which, subsequent to translocation inside the nucleus of the cell, bindsto specific regulatory DNA sequences (referred to as androgen responseelements or AREs) within the promoter or enhancer regions of the targetgene or genes present in the cell's nucleus. Other proteins termedcofactors are next recruited which bind to the amino-terminal domain orthe LBD of the receptor leading to gene transcription and subsequenttranslation to produce the protein(s) encoded by that gene or genes.

Androgen therapy has been used in the clinic to treat a variety of maledisorders, such as reproductive disorders and primary or secondary malehypogonadism. Moreover, a number of natural or synthetic AR agonistshave been clinically investigated for the treatment of musculoskeletaldisorders, such as bone disease, hematopoietic disorders, neuromusculardisease, rheumatological disease, wasting disease, and for hormonereplacement therapy (HRT), such as female androgen deficiency. Inaddition, AR antagonists, such as flutamide and bicalutamide, have beenused to treat prostate cancer. It would therefore be useful to haveavailable compounds that can activate (“agonize”) the function of the ARin a tissue-selective manner which would afford the desired beneficialosteo- and myoanabolic effects of androgens but without the negativeandrogenic properties, such as virilization and induction of anatherogenic lipid profile which can lead to cardiovascular disease.

The role of androgens in bone formation has been documented. Forexample, anabolic steroids, such as nandrolone decanoate or stanozolol,have been shown to increase bone mass in postmenopausal women. Thebeneficial effects of androgens on bone in postmenopausal osteoporosiswere documented in recent studies using combined testosterone andestrogen administration [Hofbauer, et al., “Androgen effects on bonemetabolism: recent progress and controversies,” Eur. J. Endocrinol. 140:271-286 (1999)]. Combined treatment significantly increased the rate andextent of the rise in bone mineral density (BMD) in the lumbar and hipregions, relative to treatment with estrogen alone. Additionally,estrogen-progestin combinations that incorporated an androgenicprogestin (such as norethindrone), rather than medroxyprogesteroneacetate, yielded greater improvements in hip BMD. These results haverecently been confirmed in a larger 2-year, double-blind comparisonstudy in which oral conjugated estrogen (CEE) and methyltestosteronecombinations were demonstrated to be effective in promoting accrual ofbone mass in the spine and hip, while conjugated estrogen therapy aloneprevented bone loss [“A two-year, double-blind comparison ofestrogen-androgen and conjugated estrogens in surgically menopausalwomen: Effects on bone mineral density, symptoms and lipid profiles,” J.Reprod. Med., 44: 1012-1020 (1999)]. Despite the beneficial effects ofandrogens in postmenopausal women, the use of androgens has been limitedbecause of the undesirable virilizing and metabolic action of androgens.The data from Watts and colleagues demonstrate that hot flushes decreasein women treated with CEE and methyltestosterone; however, 30% of thesewomen suffered from significant increases in acne and facial hair, acomplication of all current androgen pharmacotherapies [Watts, et al.,“Comparison of oral estrogens and estrogens plus androgen on bonemineral density, menopausal symptoms, and lipid-lipoprotein profiles insurgical menopause,” Obstet. Gynecol., 85: 529-537 (1995)]. Moreover,the addition of methyltestosterone to CEE markedly decreased HDL levels,as seen in other studies. Therefore, non-tissue selective AR agonistsmay increase the risk of cardiovascular disease. Thus, the virilizingpotential and negative effects on lipid profile of current androgentherapies provide a strong rationale for developing tissue-selectiveandrogen receptor agonists for bone. Reference is made to J. A. Kanis,“Other agents for generalized osteoporosis,” in Osteoporosis, BlackwellScience, Ch. 8, pp 196-227 (1994) for a discussion of non-selectiveanabolic steroids in the treatment of osteoporosis.

It is also well established that androgens play an important role inbone metabolism in men, which parallels the role of estrogens in women[Anderson, et al., “Androgen supplementation in eugonadal men withosteoporosis—effects of six months of treatment on bone mineral densityand cardiovascular risk factors,” Bone, 18: 171-177 (1996)]. Even ineugonadal men with established osteoporosis, the therapeutic response totestosterone treatment provided additional evidence that androgens exertimportant osteoanabolic effects. Mean lumbar BMD increased from 0.799gm/cm² to 0.839 g/cm², in 5 to 6 months in response to 250 mg oftestosterone ester administered intramuscularly every fortnight. Acommon scenario for androgen deficiency occurs in men with stage Dprostate cancer (metastatic) who undergo androgen deprivation therapy(ADT). Endocrine orchiectomy is achieved by long acting GnRH agonists,while androgen receptor blockade is implemented with flutamide,nilutamide, bicalutamide, or RU 58841 (AR antagonists). In response tohormonal deprivation, these men suffered from hot flushes, significantbone loss, weakness, and fatigue. In a recent pilot study of men withstage D prostate cancer, osteopenia (50% vs. 38%) and osteoporosis (38%vs. 25%) were more common in men who had undergone ADT for greater thanone year than the patients who did not undergo ADT [Wei, et al.,“Androgen deprivation therapy for prostate cancer results in significantloss of bone density,” Urology, 54: 607-611 (1999)]. Lumbar spine BMDwas significantly lower in men who had undergone ADT. Thus, in additionto the use of tissue selective AR agonists for osteoporosis, tissueselective AR antagonists in the prostate that lack antagonistic actionin bone and muscle may be useful agents for the treatment of prostatecancer, either alone or as an adjunct to traditional ADT such as with aGnRH agonist/antagonist [See also A. Stoch, et al., J. Clin. Endocrin.Metab., 86: 2787-2791 (2001)]. Tissue-selective AR antagonists may alsohave utility in the treatment of polycystic ovarian syndrome inpostmenopausal women [see C. A. Eagleson, et al., “Polycystic ovariansyndrome: evidence that flutamide restores sensitivity of thegonadotropin-releasing hormone pulse generator to inhibition byestradiol and progesterone,” J. Clin. Endocrinol. Metab., 85: 4047-4052(2000) and E. Diamanti-Kandarakis, “The Effect of a Pure AntiandrogenReceptor Blocker, Flutamide, on the Lipid Profile in the PolycysticOvary Syndrome,” Int. J. Endocrinol. Metab., 83: 2699-2705 (1998).

There is a need for more effective agents to treat osteopenia andosteoporosis in both men and women. Osteoporosis is characterized bybone loss, resulting from an imbalance between bone resorption(destruction) and bone formation, which starts in the fourth decade andcontinues throughout life at the rate of about 1-4% per year [Eastell,“Treatment of postmenopausal osteoporosis,” New Engl. J. Med., 338: 736(1998)]. In the United States, there are currently about 20 millionpeople with detectable fractures of the vertebrae due to osteoporosis.In addition, there are about 250,000 hip fractures per year due toosteoporosis, associated with a 12%-20% mortality rate within the firsttwo years, while 30% of patients require nursing home care after thefracture and many never become fully ambulatory again. In postmenopausalwomen, estrogen deficiency leads to increased bone resorption resultingin bone loss in the vertebrae of around 5% per year, immediatelyfollowing menopause. Thus, first line treatment/prevention of thiscondition is inhibition of bone resorption by bisphosphonates,estrogens, selective estrogen receptor modulators (SERMs), andcalcitonin. However, inhibitors of bone resorption are not sufficient torestore bone mass for patients who have already lost a significantamount of bone. The increase in spinal BMD attained by bisphosphonatetreatment can reach 11% after 7 years of treatment with alendronate. Inaddition, as the rate of bone turnover differs from site to site, higherin the trabecular bone of the vertebrae than in the cortex of the longbones, the bone resorption inhibitors are less effective in increasinghip BMD and preventing hip fracture. Therefore, osteoanabolic agents,which increase cortical bone formation and bone mass of long bones bystimulating periosteal bone formation, would address an unmet need inthe treatment of osteoporosis especially for patients with high risk ofhip fractures. The osteoanabolic agents also complement the boneresorption inhibitors that target the trabecular envelope, leading to abiomechanically favorable bone structure (Schmidt, et al., “Anabolicsteroid: Steroid effects on bone in women,” In: J. P. Bilezikian, etal., Ed., Principles of Bone Biology, San Diego: Academic Press, 1996).Tissue-selective AR agonists with diminished deleterious effects on thecardiovascular system and limited virilizing potential may be useful asa monotherapy for the prevention and/or treatment of femaleosteoporosis. In addition, a compound with osteoanabolic properties inbone and muscle but with reduced activity in the prostate and sexaccessory tissues may be useful for the prevention and/or treatment ofmale osteoporosis and osteopenia in men, particularly elderly men.

Selective androgen receptor modulators may also be useful to treatcertain hematopoietic disorders. It is known that androgens stimulaterenal hypertrophy and erythropoietin (EPO) production. Prior to theintroduction of recombinant human EPO, androgens were employed to treatanemia caused by chronic renal failure. In addition, androgens atpharmacological doses were found to increase serum EPO levels in anemicpatients with non-severe aplastic anemia and myelodysplastic syndromesbut not in non-anemic patients. Treatment modalities for anemia willrequire selective action such as may be provided by selective androgenreceptor modulators.

Furthermore, selective androgen receptor modulators may also haveclinical value as an adjunct to the treatment of obesity. This approachto lowering body fat is supported by published observations thatandrogen administration reduced subcutaneous and visceral abdominal fatin obese men [J. C. Lovejoy, et al., “Oral anabolic steroid treatment,but not parenteral androgen treatment, decreases abdominal fat in obese,older men,” Int. J. Obesity, 19: 614-624 (1995)]. Therefore, SARMsdevoid of androgenic effects on prostate may be beneficial in thetreatment of obese men. In a separate study, androgen administrationresulted in loss of subcutaneous abdominal fat in obese postmenopausalwomen [J. C. Lovejoy, et al., “Exogenous Androgens Influence BodyComposition and Regional Body Fat Distribution in Obese PostmenopausalWomen—A Clinical Research Center Study,” J. Clin. Endocrinol. Metab.,81: 2198-2203 (1996)]. In the latter study, nandrolone decanoate, a weakandrogen and anabolic agent, was found to increase lean body mass andresting metabolic rate in obese postmenopausal women consuming aweight-reducing diet.

Non-steroidal compounds having androgen receptor modulating propertieswere disclosed in U.S. Pat. Nos. 5,688,808; 5,696,130; 6,017,924;6,093,821; WO 01/16139 (published 8 Mar. 2001); and WO 01/16108(published 8 Mar. 2001), all assigned to Ligand Pharmaceuticals, and inWO 01/27086, assigned to Kaken Pharm. Co. Additional background for therationale behind the development of Selective Androgen ReceptorModulators is found in L. Zhi and E. Martinborough in Ann. Rep. Med.Chem. 36: 169-180 (2001). Non-steroidal SARMs were disclosed in J. P.Edwards, “New Nonsteroidal Androgen Receptor Modulators Based on4-(Trifluoromethyl)-2(1H)-Pyrrolidino[3,2-g]quinolinone,” Bioorg. Med.Chem. Lett., 8: 745-750 (1998) and in L. Zhi et al., “Switching AndrogenReceptor Antagonists to Agonists by Modifying C-ring Substituents onPiperidino[3,4-g]quinolinone,” Bioorg. Med. Chem. Lett., 9: 1009-1012(1999).

There exists a need in the clinical art for more effective agents thatcan elicit the positive responses of androgen replacement therapy butwithout the undesired side effects of non-tissue selective agonists ofthe AR. What is needed are compounds that can produce the same positiveresponses as androgen replacement therapy but without the undesired sideeffects. Also needed are androgenic compounds that exert selectiveeffects on different tissues of the body. In this invention, we haveidentified compounds that function as selective androgen receptormodulators (SARMs) using a series of in vitro cell-assays that profileligand mediated activation of AR, such as (i) N—C interaction, (ii)transcriptional repression, and (iii) transcriptional activation. SARMcompounds in this invention, identified with the methods listed above,exhibit tissue selective AR agonism in vivo, i.e. agonism in bone(stimulation of bone formation in a rodent model of osteoporosis) andantagonism in prostate (minimal effects on prostate growth in castratedrodents and antagonism of prostate growth induced by AR agonists).

The compounds of the present invention identified as SARMs are useful totreat diseases or conditions caused by androgen deficiency which can beameliorated by androgen administration. Such compounds are ideal for thetreatment of osteoporosis in women and men as a monotherapy or incombination with inhibitors of bone resorption, such as bisphosphonates,estrogens, SERMs, cathepsin K inhibitors, αvβ3 integrin receptorantagonists, calcitonin, and proton pump inhibitors. They can also beused with agents that stimulate bone formation, such as parathyroidhormone or analogs thereof. The SARM compounds of the present inventionmay also be employed for treatment of prostate disease, such as prostatecancer and benign prostatic hyperplasia (BPH). Moreover, compounds ofthis invention exhibit minimal effects on skin (acne and facial hairgrowth) and may be useful for treatment of hirsutism. Additionally,compounds of this invention can stimulate muscle growth and may beuseful for treatment of sarcopenia and frailty. They can be employed toreduce subcutaneous and visceral abdominal fat in the treatment ofobesity. Moreover, compounds of this invention can exhibit androgenagonism in the central nervous system and may be useful to treatvasomotor symptoms (hot flush) and to increase energy and libido,particularly in postmenopausal women. The compounds of the presentinvention may be used in the treatment of prostate cancer, either aloneor as an adjunct to traditional GnRH agonist/antagonist therapy, fortheir ability to restore bone, or as a replacement for antiandrogentherapy because of their ability to antagonize androgen in the prostate,and minimize bone depletion in the skeletal system. Further, thecompounds of the present invention may be used for their ability torestore bone in the treatment of pancreatic cancer as an adjunct totreatment with antiandrogen, or as monotherapy for their antiandrogenicproperties, offering the advantage over traditional antiandrogens ofbeing bone-sparing. Additionally, compounds of this invention canincrease the number of blood cells, such as red blood cells andplatelets, and may be useful for the treatment of hematopoieticdisorders, such as aplastic anemia. Finally, compounds of this inventionhave minimal effects on lipid metabolism. Thus, considering their tissueselective androgen receptor agonism listed above, the compounds of thisinvention are ideal for hormone replacement therapy in hypogonadic(androgen deficient) men.

It is therefore an object of the present invention to providefluorinated 4-azasteroid derivatives which are useful as selectiveandrogen receptor modulators.

It is another object of the present invention to provide pharmaceuticalcompositions comprising the fluorinated 4-azasteroid derivatives of thepresent invention in association with a pharmaceutically acceptablecarrier.

It is another object of the present invention to provide pharmaceuticalcompositions comprising the fluorinated 4-azasteroid derivatives for useas selective androgen receptor modulators.

It is another object of the present invention to provide methods for thetreatment of diseases or conditions caused by androgen deficiency whichcan be ameliorated by androgen administration.

It is another object of the present invention to provide methods for thetreatment of diseases or conditions caused by androgen deficiency whichcan be ameliorated by androgen administration in combination with otheragents.

It is another object of the present invention to provide fluorinated4-azasteroid derivatives and their pharmaceutical compositions for useas a medicament for the treatment of diseases or conditions caused byandrogen deficiency which can be ameliorated by androgen administration.

It is another object of the present invention to provide fluorinated4-azasteroid derivatives and their pharmaceutical compositions for themanufacture of a medicament for the treatment of diseases or conditionscaused by androgen deficiency which can be ameliorated by androgenadministration.

These and other objects will become readily apparent from the detaileddescription which follows.

SUMMARY OF THE INVENTION

The present invention relates to compounds of structural formula I:

or a pharmaceutically acceptable salt or an enantiomer thereof; whereinn is 0, 1 or 2;a-b represents CF═CH, CHFCH₂, or CF₂CH₂;R¹ is hydrogen, hydroxymethyl, or C₁₋₃ alkyl, wherein alkyl isunsubstituted or substituted with one to seven fluorine atoms;R² is hydrogen or C₁₋₄ alkyl;R³ is selected from

C₁₋₄ alkyl,

(CH₂)_(n)-cycloheteroalkyl, and

(CH₂)_(n)-aryl, wherein aryl is selected from

-   (1) phenyl,-   (2) naphthyl,-   (3) benzimidazolyl,-   (4) benzofuranyl,-   (5) benzothiophenyl,-   (6) benzoxazolyl,-   (7) benzothiazolyl,-   (8) benzodihydrofuranyl,-   (9) 1,3-benzodioxolyl,-   (10) 2,3-dihydro-1,4-benzodioxinyl,-   (11) indolyl,-   (12) quinolyl,-   (13) isoquinolyl,-   (14) furanyl,-   (15) thienyl,-   (16) imidazolyl,-   (17) oxazolyl,-   (18) thiazolyl,-   (19) isoxazolyl,-   (20) isothiazolyl,-   (21) pyrazolyl,-   (22) pyrrolyl,-   (23) pyridyl,-   (24) pyrimidyl,-   (25) pyrazinyl,-   (26) thiadiazolyl,-   (27) oxadiazolyl,-   (28) triazolyl,-   (29) tetrazolyl, and-   (30) indanyl;    wherein the alkyl group or the cycloheteroalkyl group is    unsubstituted or substituted with one to three substituents    independently selected from halogen, hydroxy, and C₁₋₄ alkoxy; the    aryl group as defined in items (1) to (30) is unsubstituted or    substituted with one to three groups independently selected from    halogen, phenyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,    phenyl-C₁₋₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆ alkylamino-C₀₋₆ alkyl,    (C₁₋₆ alkyl)₂amino-C₀₋₆ alkyl, phenyl-C₀₋₆ alkylamino-C₀₋₆ alkyl,    (phenyl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆ alkylthio, phenyl-C₀₋₆    alkylthio, C₁₋₆ alkylsulfinyl, phenyl-C₀₋₆ alkylsulfinyl, C₁₋₆    alkylsulfonyl, phenyl-C₀₋₆ alkylsulfonyl,    C₁₋₆ alkoxy-C₀₋₆ alkyl, phenyl-C₀₋₆ alkoxy-C₀₋₆ alkyl,    hydroxycarbonyl-C₀₋₆ alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl,    phenyl-C₀₋₆ alkoxycarbonyl-C₀₋₆ alkyl, hydroxycarbonyl-C₁₋₆    alkyloxy, hydroxy-C₀₋₆ alkyl, cyano, nitro, perfluoro-C₁₋₄ alkyl,    perfluoro-C₁₋₄ alkoxy, oxo, C₁₋₆ alkylcarbonyloxy, phenyl-C₀₋₆    alkylcarbonyloxy, C₁₋₆ alkylcarbonylamino, phenyl-C₀₋₆    alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, phenyl-C₀₋₆    alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, phenyl-C₀₋₆    alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, phenyl-C₀₋₆    alkylaminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino,    (phenyl-C₀₋₆ alkyl)₂ aminocarbonylamino, (C₁₋₆ alkyl)₂    aminocarbonyloxy, and (phenyl-C₀₋₆ alkyl)₂ aminocarbonyloxy; and    wherein any methylene (CH₂) carbon atom in (CH₂)_(n) is    unsubstituted or substituted with one to two groups independently    selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents    when on the same methylene (CH₂) group are taken together with the    carbon atom to which they are attached to form a cyclopropyl group;    or R² and R³ together form a 5- or 6-membered saturated ring fused    with a 5- or 6-membered aromatic ring system having 0, 1, or 2    heteroatoms selected from N, O, and S.

These compounds are effective as androgen receptor agonists and areparticularly effective as selective androgen receptor agonists (SARMs).They are therefore useful for the treatment of conditions caused byandrogen deficiency or which can be ameliorated by androgenadministration.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment ofconditions caused by androgen deficiency or which can be ameliorated byandrogen administration in a mammal in need thereof by administering thecompounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for the treatment ofosteoporosis, osteopenia, glucocorticoid-induced osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and otherhematopoietic disorders, arthritic conditions, such as for example,inflammatory arthritis and joint repair, HIV-wasting, prostate cancer,cancer cachexia, muscular dystrophies, premature ovarian failure, andautoimmune disease by administering the compounds and pharmaceuticalcompositions of the present invention, alone or in combination with atherapeutically effective amount of another agent known to be useful totreat these conditions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are useful as androgenreceptor agonists, in particular, as selective androgen receptoragonists. Compounds of the present invention are described by structuralformula I:

or a pharmaceutically acceptable salt or an enantiomer thereof; whereinn is 0, 1 or 2;a-b represents CF═CH, CHFCH₂, or CF₂CH₂;R¹ is hydrogen, hydroxymethyl, or C₁₋₃ alkyl, wherein alkyl isunsubstituted or substituted with one to seven fluorine atoms;R² is hydrogen or C₁₋₄ alkyl;R³ is selected from

C₁₋₄ alkyl,

(CH₂)_(n)-cycloheteroalkyl, and

(CH₂)_(n)-aryl, wherein aryl is selected from

-   (1) phenyl,-   (2) naphthyl,-   (3) benzimidazolyl,-   (4) benzofuranyl,-   (5) benzothiophenyl,-   (6) benzoxazolyl,-   (7) benzothiazolyl,-   (8) benzodihydrofuranyl,-   (9) 1,3-benzodioxolyl,-   (10) 2,3-dihydro-1,4-benzodioxinyl,-   (11) indolyl,-   (12) quinolyl,-   (13) isoquinolyl,-   (14) furanyl,-   (15) thienyl,-   (16) imidazolyl,-   (17) oxazolyl,-   (18) thiazolyl,-   (19) isoxazolyl,-   (20) isothiazolyl,-   (21) pyrazolyl,-   (22) pyrrolyl,-   (23) pyridyl,-   (24) pyrimidyl,-   (25) pyrazinyl,-   (26) thiadiazolyl,-   (27) oxadiazolyl,-   (28) triazolyl,-   (29) tetrazolyl, and-   (30) indanyl;    wherein the alkyl group or the cycloheteroalkyl group is    unsubstituted or substituted with one to three substituents    independently selected from halogen, hydroxy, and C₁₋₄ alkoxy; the    aryl group as defined in items (1) to (30) is unsubstituted or    substituted with one to three groups independently selected from    halogen, phenyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,    phenyl-C₁₋₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆ alkylamino-C₀₋₆ alkyl,    (C₁₋₆ alkyl)₂amino-C₀₋₆ alkyl, phenyl-C₀₋₆ alkylamino-C₀₋₆ alkyl,    (phenyl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆ alkylthio, phenyl-C₀₋₆    alkylthio, C₁₋₆ alkylsulfinyl, phenyl-C₀₋₆ alkylsulfinyl, C₁₋₆    alkylsulfonyl, phenyl-C₀₋₆ alkylsulfonyl,    C₁₋₆ alkoxy-C₀₋₆ alkyl, phenyl-C₀₋₆ alkoxy-C₀₋₆ alkyl,    hydroxycarbonyl-C₀₋₆ alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl,    phenyl-C₀₋₆ alkoxycarbonyl-C₀₋₆ alkyl, hydroxycarbonyl-C₁₋₆    alkyloxy, hydroxy-C₀₋₆ alkyl, cyano, nitro, perfluoro-C₁₋₄ alkyl,    perfluoro-C₁₋₄ alkoxy, oxo, C₁₋₆ alkylcarbonyloxy, phenyl-C₀₋₆    alkylcarbonyloxy, C₁₋₆ alkylcarbonylamino, phenyl-C₀₋₆    alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, phenyl-C₀₋₆    alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, phenyl-C₀₋₆    alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, phenyl-C₀₋₆    alkylaminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino,    (phenyl-C₀₋₆ alkyl)₂ aminocarbonylamino, (C₁₋₆ alkyl)₂    aminocarbonyloxy, and (phenyl-C₀₋₆ alkyl)₂ aminocarbonyloxy; and    wherein any methylene (CH₂) carbon atom in (CH₂)_(n) is    unsubstituted or substituted with one to two groups independently    selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents    when on the same methylene (CH₂) group are taken together with the    carbon atom to which they are attached to form a cyclopropyl group;    or R² and R³ together form a 5- or 6-membered saturated ring fused    with a 5- or 6-membered aromatic ring system having 0, 1, or 2    heteroatoms selected from N, O, and S.

In one embodiment of the compounds of the present invention, R¹ ishydrogen or methyl. In a class of this embodiment, R¹ is methyl.

In a second embodiment of the compounds of the present invention, a-brepresents CF═CH.

In a third embodiment of the compounds of the present invention, a-brepresents CHFCH₂.

In a fourth embodiment of the compounds of the present invention, R² ishydrogen and R³ is (CH₂)_(n)-aryl. In a class of this embodiment, n is 0or 1.

In a fifth embodiment of the compounds of the present invention, R¹ ismethyl, a-b represents CF═CH, R² is hydrogen, and R³ is (CH₂)_(n)-aryl.In a class of this embodiment, n is 0 or 1.

In a sixth embodiment of the compounds of the present invention, R¹ ismethyl, a-b represents CHFCH₂, R² is hydrogen, and R³ is (CH₂)_(n)-aryl.In a class of this embodiment, n is 0 or 1.

In another embodiment, R¹ is chosen from hydrogen and methyl, a-b ischosen from CHFCH₂, R² is hydrogen, and R³ is(CH₂)_(n)-cycloheteroalkyl, In a class of this embodiment, R¹ is methyl,and a-b represents CF═CH.

In yet another embodiment of the invention, R³ is chosen from:

C₁₋₄ alkyl, and

(CH₂)_(n)-aryl, wherein aryl is selected from

-   (1) phenyl,-   (2) naphthyl,-   (3) benzimidazolyl,-   (4) benzofuranyl,-   (5) benzothiophenyl,-   (6) benzoxazolyl,-   (7) benzothiazolyl,-   (8) benzodihydrofuranyl,-   (9) 1,3-benzodioxolyl,-   (10) 2,3-dihydro-1,4-benzodioxinyl,-   (11) indolyl,-   (12) quinolyl,-   (13) isoquinolyl,-   (14) furanyl,-   (15) thienyl,-   (16) imidazolyl,-   (17) oxazolyl,-   (18) thiazolyl,-   (19) isoxazolyl,-   (20) isothiazolyl,-   (21) pyrazolyl,-   (22) pyrrolyl,-   (23) pyridyl,-   (24) pyrimidyl,-   (25) pyrazinyl,-   (26) thiadiazolyl,-   (27) oxadiazolyl,-   (28) triazolyl,-   (29) tetrazolyl, and-   (30) indanyl;    wherein the alkyl group or the cycloheteroalkyl group is    unsubstituted or substituted with one to three substituents    independently selected from halogen, hydroxy, and C₁₋₄ alkoxy; the    aryl group as defined in items (1) to (30) is unsubstituted or    substituted with one to three groups independently selected from    halogen, phenyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl,    phenyl-C₁₋₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆ alkylamino-C₀₋₆ alkyl,    (C₁₋₆ alkyl)₂amino-C₀₋₆ alkyl, phenyl-C₀₋₆ alkylamino-C₀₋₆ alkyl,    (phenyl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆ alkylthio, phenyl-C₀₋₆    alkylthio, C₁₋₆ alkylsulfinyl, phenyl-C₀₋₆ alkylsulfinyl, C₁₋₆    alkylsulfonyl, phenyl-C₀₋₆ alkylsulfonyl,    C₁₋₆ alkoxy-C₀₋₆ alkyl, phenyl-C₀₋₆ alkoxy-C₀₋₆ alkyl,    hydroxycarbonyl-C₀₋₆ alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl,    phenyl-C₀₋₆ alkoxycarbonyl-C₀₋₆ alkyl, hydroxycarbonyl-C₁₋₆    alkyloxy, hydroxy-C₀₋₆ alkyl, cyano, nitro, perfluoro-C₁₋₄ alkyl,    perfluoro-C₁₋₄ alkoxy, oxo, C₁₋₆ alkylcarbonyloxy, phenyl-C₀₋₆    alkylcarbonyloxy, C₁₋₆ alkylcarbonylamino, phenyl-C₀₋₆    alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, phenyl-C₀₋₆    alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, phenyl-C₀₋₆    alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, phenyl-C₀₋₆    alkylaminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino,    (phenyl-C₀₋₆ alkyl)₂ aminocarbonylamino, (C₁₋₆ alkyl)₂    aminocarbonyloxy, and (phenyl-C₀₋₆ alkyl)₂ aminocarbonyloxy; and    wherein any methylene (CH₂) carbon atom in (CH₂)_(n) is    unsubstituted or substituted with one to two groups independently    selected from halogen, hydroxy, and C₁₋₄ alkyl; or two substituents    when on the same methylene (CH₂) group are taken together with the    carbon atom to which they are attached to form a cyclopropyl group.

Illustrative but nonlimiting examples of compounds of the presentinvention that are useful as androgen receptor modulators are thefollowing:

-   N-(2,2,2-trifluoroethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-chlorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(4-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(4-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(4-chloro-2-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,4-difluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(α-methylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(phenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(4-chloro-2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-methylpyridin-2-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(thiophen-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(thiophen-3-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-trifluoromethylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(benzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(1-methylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(1-methyl-5-trifluoromethylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(thiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(4-methylthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(thiazol-4-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(1-methylimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(2-trifluoromethylphenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(3-methoxyphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(4-methoxyphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(2-trifluoromethylphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(2-chlorophenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(benzimidazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(1-methylbenzimidazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    and-   N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.

In yet another embodiment of the invention, the compounds of the presentinvention are chosen from:

-   N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    and-   N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.

In yet another variant, the compounds of the present invention arechosen from:

-   N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3H-imidazo[4,5-b]pyrdin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.

In one embodiment of the invention, the compounds are chosen from:

-   N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;-   N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;-   N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    and-   N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;    pharmaceutically acceptable salts and enantiomers thereof.

The compounds of the present invention can have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein can exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof. Here, X represents the remainder of the fluorinated4-azasteroid derivatives of the present invention.

The term “alkyl” shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term“C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence of analkyl group.

The term “alkenyl” shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term “alkynyl” shall mean straight or branched chain alkynes of twoto ten total carbon atoms, or any number within this range.

The term “alkylidene” shall mean a straight or branched chain alkylidenegroup of one to ten total carbon atoms, or any number within this range.

The term “cycloalkyl” shall mean cyclic rings of alkanes of three toeight total carbon atoms, or any number within this range (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl).

The term “cycloheteroalkyl,” as used herein, shall mean a 3- to8-membered fully saturated heterocyclic ring containing one or twoheteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groupsinclude, but are not limited to, piperidinyl, pyrrolidinyl, azetidinyl,morpholinyl, oxacyclopentane, oxacyclohexane, and piperazinyl. In oneembodiment of the present invention, cycloheteroalkyl is selected frompiperidinyl, pyrrolidinyl, oxacyclopentane, oxacyclohexane, andmorpholinyl.

The term “alkoxy,” as used herein, refers to straight or branched chainalkoxides of the number of carbon atoms specified (e.g., C₁₋₅ alkoxy),or any number within this range (i.e., methoxy, ethoxy, etc.).

The term “aryl,” as used herein, refers to a monocyclic or bicyclicsystem comprising at least one aromatic ring, wherein the monocyclic orbicyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O,or S, and wherein the monocyclic or bicyclic system is eitherunsubstituted or substituted with one or more groups independentlyselected from halogen, phenyl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, phenyl-C₁₋₁₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆alkylamino-C₀₋₆ alkyl, (C₁₋₆ alkyl)₂amino-C₀₋₆alkyl, phenyl-C₀₋₆alkylamino-C₀₋₆alkyl, (phenyl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆alkylthio, phenyl-C₀₋₆ alkylthio, C₁₋₆ alkylsulfinyl, phenyl-C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, phenyl-C₀₋₆ alkylsulfonyl, C₁₋₆alkoxy-C₀₋₆alkyl, phenyl-C₀₋₆ alkoxy-C₀₋₆ alkyl, hydroxycarbonyl-C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl, phenyl-C₀₋₆alkoxycarbonyl-C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy-C₀₋₆alkyl, cyano, nitro, perfluoroC₁₋₄ alkyl, perfluoroC₁₋₄ alkoxy, oxo,C₁₋₆ alkylcarbonyloxy, phenyl-C₀₋₆ alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, phenyl-C₀₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, phenyl-C₀₋₆ alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, phenyl-C₀₋₆ alkoxycarbonylamino, C₁₋₆alkylaminocarbonylamino, phenyl-C₀₋₆ alkylaminocarbonylamino, (C₁₋₆alkyl)₂ aminocarbonylamino, (phenyl-C₀₋₆ alkyl)₂ aminocarbonylamino,(C₁₋₆ alkyl)₂ aminocarbonyloxy, and (phenyl-C₀₋₆ alkyl)₂aminocarbonyloxy. Preferably, the aryl group is unsubstituted, mono-,di-, or tri-substituted with one to three of the above-namedsubstituents; more preferably, the aryl group is unsubstituted, mono- ordi-substituted with one to two of the above-named substituents.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The terms “arylalkyl” and “alkylaryl” include an alkyl portion wherealkyl is as defined above and include an aryl portion where aryl is asdefined above. Examples of arylalkyl include, but are not limited to,benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, andthienylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

The term “halogen” shall include iodine, bromine, chlorine, andfluorine.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

When any variable (e.g., R², R³, etc.) occurs more than one time in anysubstituent or in formula I, its definition in each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², R³,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity.

Compounds of the present invention have been found to betissue-selective modulators of the androgen receptor (SARMs). In oneaspect, compounds of the present invention may be useful to activate thefunction of the androgen receptor in a mammal, and in particular toactivate the function of the androgen receptor in bone and/or muscletissue and block or inhibit (“antagonize”) the function of the androgenreceptor in the prostate of a male individual or in the uterus of afemale individual. The activation of the AR in bone can be assayedthrough stimulation of bone formation in a rodent model of osteoporosis,and the antagonism of the AR in the prostate can be assayed throughobservation of minimal effects on prostate growth in castrated rodentsand antagonism of prostate growth induced by AR agonists, as detailed inthe Examples.

A further aspect of the present invention is concerned with compounds ofstructural formula I that block the function of the androgen receptor inthe prostate of a male individual or in the uterus of a femaleindividual induced by AR agonists, but not in hair-growing skin or vocalcords, and activate the function of the androgen receptor in bone and/ormuscle tissue, but not in organs which control blood lipid levels (e.g.liver).

The compounds of the present invention may be used to treat conditionswhich are caused by androgen deficiency or which can be ameliorated byandrogen replacement, including, but not limited to osteoporosis,osteopenia, glucocorticoid-induced osteoporosis, periodontal disease,bone fracture, bone damage following bone reconstructive surgery,sarcopenia, frailty, aging skin, male hypogonadism, postmenopausalsymptoms in women, atherosclerosis, hypercholesterolemia,hyperlipidemia, obesity, aplastic anemia and other hematopoieticdisorders, arthritic conditions, such as for example, inflammatoryarthritis and joint repair, HIV-wasting, prostate cancer, cancercachexia, muscular dystrophies, premature ovarian failure, andautoimmune disease, alone or in combination with other active agents.Treatment is effected by administration of a therapeutically effectiveamount of a compound of structural formula I to a mammal in need of suchtreatment. In addition, these compounds are useful as ingredients inpharmaceutical compositions alone or in combination with other activeagents.

In one embodiment, the compounds of the present invention may be used totreat conditions in a male individual which are caused by androgendeficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,prostate cancer, cancer cachexia, obesity, aplastic and other anemias,and muscular dystrophies, alone or in combination with other activeagents. Treatment is effected by administration of a therapeuticallyeffective amount of a compound of structural formula I to a maleindividual in need of such treatment.

“Arthritic condition” or “arthritic conditions” refers to a diseasewherein inflammatory lesions are confined to the joints or anyinflammatory conditions of the joints, most notably osteoarthitis andrheumatoid arthritis (Academic Press Dictionary of Science Technology;Academic Press; 1st edition, Jan. 15, 1992). The compounds of Formula Iare also useful, alone or in combination, to treat or prevent arthriticconditions, such as Behcet's disease; bursitis and tendinitis; CPPDdeposition disease; carpal tunnel syndrome; Ehlers-Danlos syndrome;fibromyalgia; gout; infectious arthritis; inflammatory bowel disease;juvenile arthritis; lupus erythematosus; lyme disease; marfan syndrome;myositis; osteoarthritis; osteogenesis imperfecta; osteonecrosis;polyarteritis; polymyalgia rheumatica; psoriatic arthritis; Raynaud'sphenomenon; reflex sympathetic dystrophy syndrome; Reiter's syndrome;rheumatoid arthritis; scleroderma; and Sjogren's syndrome. An embodimentof the invention encompasses the treatment or prevention of an arthriticcondition which comprises administering a therapeutically effectiveamount of a Compound of Formula I. A subembodiment is the treatment orprevention of osteoarthritis which comprises administering atherapeutically effective amount of a Compound of Formula I. See: CutoloM, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Ann. N.Y.Acad. Sci. 2002 June; 966:131-42; Cutolo, M. Rheum Dis Clin North Am2000 November; 26 (4):881-95; Bijlsma J W, Van den Brink H R. Am JReprod Immunol 1992 October-December; 28 (3-4):231-4; Jansson L,Holmdahl R.; Arthritis Rheum 2001 September; 44 (9):2168-75; and PurdieD W. Br Med Bull 2000; 56 (3):809-23. Also, see Merck Manual, 17thedition, pp. 449-451.

When used in combination to treat arthritic conditions, the Compounds ofFormula I can be used with any of the drugs disclosed herein as usefulfor combination therapy, or can be used with drugs known to treat orprevent arthritic conditions, such as corticosteroids, cytoxic drugs (orother disease modifying or remission inducing drugs), gold treatment,methotrexate, NSAIDs, and COX-2 inhibitors.

In another embodiment, the compounds of the present invention may beused to treat conditions in a female individual which are caused byandrogen deficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, postmenopausal symptoms,periodontal disease, HIV-wasting, cancer cachexia, obesity, aplastic andother anemias, muscular dystrophies, premature ovarian failure, andautoimmune disease, alone or in combination with other active agents.Treatment is effected by administration of a therapeutically effectiveamount of a compound of structural formula I to a female individual inneed of such treatment.

The compounds of structural formula I may also be employed as adjunctsto traditional androgen depletion therapy in the treatment of prostatecancer to restore bone, minimize bone loss, and maintain or increasebone mineral density. In this manner, they may be employed together withtraditional androgen deprivation therapy, including GnRHagonists/antagonists, such as those disclosed in P. Limonta, et al.,“LHRH analogues as anticancer agents: pituitary and extrapituitary sitesof action,” Exp. Opin. Invest. Drugs, 10: 709-720 (2001); H. J.Stricker, “Luteinizing hormone-releasing hormone antagonists,” Urology,58 (Suppl. 2A): 24-27 (2001); R. P. Millar, et al., “Progress towardsthe development of non-peptide orally-active GnRH antagonists,” BritishMedical Bulletin, 56: 761-772 (2000); and A. V. Schally et al.,“Rational use of agonists and antagonists of LH-RH in the treatment ofhormone-sensitive neoplasms and gynecologic conditions,” Advanced DrugDelivery Reviews, 28: 157-169 (1997). It is also possible that thecompounds of structural formula I may be used in combination withantiandrogens, such as flutamide, 2-hydroxyflutamide (the activemetabolite of flutamide), nilutamide, and bicalutamide (Casodex™) in thetreatment of prostate cancer.

Further, the compounds of the present invention may also be employed inthe treatment of pancreatic cancer, either for their androgen antagonistproperties or as an adjunct to an antiandrogen, such as flutamide,2-hydroxyflutamide (the active metabolite of flutamide), nilutamide, andbicalutamide (Casodex™).

Compounds of structural formula I have minimal negative effects on lipidmetabolism. Therefore, considering their tissue selective androgenagonistic properties, the compounds of this invention have advantagesover existing approaches for hormone replacement therapy in hypogonadic(androgen deficient) male individuals.

Additionally, compounds of the present invention can increase the numberof blood cells, such as red blood cells and platelets, and can be usedfor treatment of hematopoietic disorders, such as aplastic anemia.

Representative compounds of the present invention typically displaysubmicromolar binding affinity for the androgen receptor. Compounds ofthis invention are therefore useful in treating mammals suffering fromdisorders related to androgen receptor function. Pharmacologicallyeffective amounts of the compound, including the pharmaceuticallyeffective salts thereof, are administered to the mammal, to treatdisorders related to androgen receptor function, or which can beimproved by the addition of additional androgen, such as osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and otherhematopoietic disorders, pancreatic cancer, arthritic conditions, forexample, inflammatory arthritis, and joint repair.

It is generally preferable to administer compounds of the presentinvention in their enantiomerically pure form. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

As used herein, a compound of the present invention which functions asan “agonist” of the androgen receptor can bind to the androgen receptorand initiate a physiological or a pharmacological responsecharacteristic of that receptor. The term “tissue-selective androgenreceptor modulator” refers to an androgen receptor ligand that mimicsthe action of a natural ligand in some tissues but not in others. A“partial agonist” is an agonist which is unable to induce maximalactivation of the receptor population, regardless of the amount ofcompound applied. A “full agonist” induces full activation of theandrogen receptor population at a given concentration. A compound of thepresent invention which functions as an “antagonist” of the androgenreceptor can bind to the androgen receptor and block or inhibit theandrogen-associated responses normally induced by a natural androgenreceptor ligand.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant that the carrier, diluentor excipient must be compatible with the other ingredients of theformulation and not be deleterious to the recipient thereof.

The terms “administration of a compound” and “administering a compound”should be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the individual in need oftreatment.

By the term “modulating a function mediated by the androgen receptor ina tissue selective manner” is meant modulating a function mediated bythe androgen receptor selectively (or discriminately) in anabolic (boneand/or muscular) tissue (bone and muscular) in the absence of suchmodulation at androgenic (reproductive) tissue, such as the prostate,testis, seminal vesicles, ovary, uterus, and other sex accessorytissues. In one embodiment the function of the androgen receptor inanabolic tissue is activated whereas the function of the androgenreceptor in androgenic tissue is blocked or suppressed.

The administration of a compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well-known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration, other drugs and treatments which the patientmay concomitantly require, and other factors in the physician'sjudgment.

Generally, the daily dosage of a compound of structural formula I may bevaried over a wide range from 0.01 to 1000 mg per adult human per day.Most preferably, dosages range from 0.1 to 200 mg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175,180, 200, 225, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the mammal to be treated.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through an intravenous solution, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Formulations of the tissue-selective androgen receptor modulatoremployed in the present method for medical use comprise a compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not being deleterious to therecipient subject of the formulation.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of structural formula I together witha pharmaceutically acceptable carrier thereof.

The formulations include those suitable for oral, rectal, intravaginal,topical or parenteral (including subcutaneous, intramuscular andintravenous administration). Preferred formulations are those suitablefor oral administration.

The formulations may be presented in a unit dosage form and may beprepared by any of the methods known in the art of pharmacy. All methodsinclude the step of bringing the active compound in association with acarrier which constitutes one or more ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into the desired dosage form.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets may be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavoredsuspending or dispersing agents such as the synthetic and natural gums,for example, tragacanth, acacia, methyl cellulose and the like, may bemade by adding the active compound to the solution or suspension.Additional dispersing agents which may be employed include glycerin andthe like.

Formulations for vaginal or rectal administration may be presented as asuppository with a conventional carrier, i.e., a base that is nontoxicand nonirritating to mucous membranes, compatible with a compound ofstructural formula I, and is stable in storage and does not bind orinterfere with the release of the compound of structural formula I.Suitable bases include: cocoa butter (theobroma oil), polyethyleneglycols (such as carbowax and polyglycols), glycol-surfactantcombinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acidesters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, andhydrogenated vegetable oils. When glycerinated gelatin suppositories areused, a preservative such as methylparaben or propylparaben may beemployed.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulationsthat comprise a sterile aqueous preparation of the active compound whichis preferably isotonic with the blood of the recipient. Suchformulations suitably comprise a solution or suspension of a compoundthat is isotonic with the blood of the recipient subject. Suchformulations may contain distilled water, 5% dextrose in distilled wateror saline and the active compound. Often it is useful to employ apharmaceutically and pharmacologically acceptable acid addition salt ofthe active compound that has appropriate solubility for the solventsemployed. Useful formulations also comprise concentrated solutions orsolids comprising the active compound which on dilution with anappropriate solvent give a solution suitable for parenteraladministration.

The compounds of the present invention may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates, and cross-linked or amphipathic block copolymers ofhydrogels.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds usually appliedin the treatment of the above mentioned conditions, includingosteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, aplastic anemia and otherhematopoietic disorders, pancreatic cancer, arthritic conditions, suchas inflammatory arthritis, and joint repair.

For the treatment and prevention of osteoporosis, the compounds of thepresent invention may be administered in combination with abone-strengthening agent selected from antiresorptive agents,osteoanabolic agents, and other agents beneficial for the skeletonthrough mechanisms which are not precisely defined, such as calciumsupplements, flavonoids, and vitamin D analogs. The conditions ofperiodontal disease, bone fracture, and bone damage following bonereconstructive surgery may also benefit from these combined treatments.For example, the compounds of the instant invention may be effectivelyadministered in combination with effective amounts of other agents suchas estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, αxβ3integrin receptor antagonists, vacuolar ATPase inhibitors, thepolypeptide osteoprotegerin, antagonists of VEGF, thiazolidinediones,calcitonin, protein kinase inhibitors, parathyroid hormone (PTH) andanalogs, calcium receptor antagonists, growth hormone secretagogues,growth hormone releasing hormone, insulin-like growth factor, bonemorphogenetic protein (BMP), inhibitors of BMP antagonism, prostaglandinderivatives, fibroblast growth factors, vitamin D and derivativesthereof, vitamin K and derivatives thereof, soy isoflavones, calciumsalts, and fluoride salts. The conditions of periodontal disease, bonefracture, and bone damage following bone reconstructive surgery may alsobenefit from these combined treatments. In one embodiment of the presentinvention, a compound of the instant invention may be effectivelyadministered in combination with an effective amount of abone-strengthening agent selected from estrogen or an estrogenderivative, alone or in combination with a progestin or progestinderivative; a bisphosphonate; an antiestrogen or a selective estrogenreceptor modulator; an αvβ3 integrin receptor antagonist; a cathepsin Kinhibitor; an osteoclast vacuolar ATPase inhibitor; calcitonin; andosteoprotegerin.

In the treatment of osteoporosis, the activity of the compounds of thepresent invention are distinct from that of the anti-resorptive agents:estrogens, bisphosphonates, SERMs, calcitonin, cathepsin K inhibitors,vacuolar ATPase inhibitors, agents interfering with theRANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any otherinhibitors of osteoclast generation or osteoclast activation. Ratherthan inhibiting bone resorption, the compounds of structural formula Istimulate bone formation, acting preferentially on cortical bone, whichis responsible for a significant part of bone strength. The thickeningof cortical bone substantially contributes to a reduction in fracturerisk, especially fractures of the hip. The combination of thetissue-selective androgen receptor modulators of structural formula Iwith anti-resorptive agents such as estrogen, bisphosphonates,antiestrogens, SERMs, calcitonin, αvβ3 integrin receptor antagonists,HMG-CoA reductase inhibitors, vacuolar ATPase inhibitors, and cathepsinK inhibitors is particularly useful because of the complementarity ofthe bone anabolic and antiresorptive actions.

Bone antiresportive agents are those agents which are known in the artto inhibit the resorption of bone and include, for example, estrogen andestrogen derivatives which include steroidal compounds having estrogenicactivity such as, for example, 17β-estradiol, estrone, conjugatedestrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol, and thelike. The estrogen or estrogen derivative may be employed alone or incombination with a progestin or progestin derivative. Nonlimitingexamples of progestin derivatives are norethindrone andmedroxy-progesterone acetate.

Bisphosphonates are also bone anti-resorptive agents. Bisphosphonatecompounds which may also be employed in combination with a compound ofstructural formula I of the present invention include:

-   (a) alendronic acid: (4-amino-1-hydroxybutylidene)-bis-phosphonic    acid;-   (b) alendronate (also known as alendronate sodium or monosodium    trihydrate): (4-amino-1-hydroxybutylidene)-bis-phosphonate    monosodium trihydrate (alendronic acid and alendronate are described    in U.S. Pat. Nos. 4,922,007, to Kieczykowski et al., issued May 1,    1990, and 5,019,651, to Kieczykowski, issued May 28, 1991, both of    which are incorporated by reference herein in their entirety);-   (c) [(cycloheptylamino)-methylene]-bis-phosphonate (incadronate),    which is described in U.S. Pat. No. 4,970,335, to Isomura et al.,    issued Nov. 13, 1990, which is incorporated by reference herein in    its entirety;-   (d) (dichloromethylene)-bis-phosphonic acid (clodronic acid) and the    disodium salt (clodronate), which are described in Belgium Patent    672,205 (1966) and J. Org. Chem. 32, 4111 (1967), both of which are    incorporated by reference herein in their entirety;-   (e) [1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bis-phosphonate    (EB-1053);-   (f) (1-hydroxyethylidene)-bis-phosphonate (etidronate);-   (g) [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate    (ibandronate), which is described in U.S. Pat. No. 4,927,814, issued    May 22, 1990, which is incorporated by reference herein in its    entirety;-   (h) (6-amino-1-hydroxyhexylidene)-bis-phosphonate (neridronate);-   (i) [3-(dimethylamino)-1-hydroxypropylidene]-bis-phosphonate    (olpadronate);-   (j) (3-amino-1-hydroxypropylidene)-bis-phosphonate (pamidronate);-   (k) [2-(2-pyridinyl)ethylidene]-bis-phosphonate (piridronate), which    is described in U.S. Pat. No. 4,761,406, which is incorporated by    reference in its entirety;-   (l) [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate    (risedronate);-   (m) {[(4-chlorophenyl)thio]methylene}-bis-phosphonate (tiludronate),    which is described in U.S. Pat. No. 4,876,248, to Breliere et al.,    Oct. 24, 1989, which is incorporated by reference herein in its    entirety;-   (n) [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bis-phosphonate    (zoledronate); and-   (o)    [1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bis-phosphonate    (minodronate).

In one embodiment of the methods and compositions of the presentinvention, the bisphosphonate is selected from alendronate, clodronate,etidronate, ibandronate, incadronate, minodronate, neridronate,olpadronate, pamidronate, piridronate, risedronate, tiludronate, andzoledronate, and pharmaceutically acceptable salts thereof, and mixturesthereof. In a class of this embodiment, the bisphosphonate is selectedfrom alendronate, risedronate, zoledronate, ibandronate, tiludronate,and clodronate. In a subclass of this class, the bisphosphonate isalendronate, pharmaceutically acceptable salts and hydrates thereof, andmixtures thereof. A particular pharmaceutically acceptable salt ofalendronate is alendronate monosodium. Pharmaceutically acceptablehydrates of alendronate monosodium include the monohydrate and thetrihydrate. A particular pharmaceutically acceptable salt of risedronateis risedronate monosodium. Pharmaceutically acceptable hydrates ofrisedronate monosodium include the hemi-pentahydrate.

As used throughout this specification and claims, the term “alendronicacid” includes the related bisphosphonic acid forms, pharmaceuticallyacceptable salt forms, and equilibrium mixtures of these. It includescrystalline, hydrated crystalline, and amorphous forms of alendronicacid and pharmaceutically acceptable salts thereof. It specificallyincludes anhydrous alendronate monosodium, alendronate monosodiummonohydrate, and alendronate monosodium trihydrate.

Still further, antiestrogenic compounds such as raloxifene (see, e.g.,U.S. Pat. No. 5,393,763), clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55, 945-27, Mer-25, U-11,555A, U-100A,and salts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) may be employed in combination with a compound of structuralformula I in the methods and compositions of the present invention.These agents are also known as SERMs, or selective estrogen receptormodulators, agents known in the art to prevent bone loss by inhibitingbone resorption via pathways believed to be similar to those ofestrogens. These agents may be used in combination with the compounds ofthe present invention to beneficially treat bone disorders includingosteoporosis. Such agents include, for example, tamoxifen, raloxifene,lasofoxifene, toremifene, azorxifene, EM-800, EM-652, TSE 424,clomiphene, droloxifene, idoxifene, and levormeloxifene [Goldstein, etal., “A pharmacological review of selective estrogen receptormodulators,” Human Reproduction Update, 6: 212-224 (2000), and Lufkin,et al., “The role of selective estrogen receptor modulators in theprevention and treatment of osteoporosis,” Rheumatic Disease Clinics ofNorth America, 27: 163-185 (2001)]. SERMs are also discussed in“Targeting the Estrogen Receptor with SERMs,” Ann. Rep. Med. Chem.36:149-158 (2001).

αvβ3 Integrin receptor antagonists suppress bone resorption and may beemployed in combination with the tissue selective androgen receptormodulators of structural formula I for the treatment of bone disordersincluding osteoporosis. Peptidyl as well as peptidomimetic antagonistsof the αvβ3 integrin receptor have been described both in the scientificand patent literature. For example, reference is made to W. J. Hoekstraand B. L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) and referencescited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO98/30542; WO 99/15506; WO 99/15507; WO 00/03973; EP 853084; EP 854140;EP 854145; U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796;5,780,426; 5,929,120; 5,952,341; 6,017,925; and 6,048,861. Evidence ofthe ability of αvβ3 integrin receptor antagonists to prevent boneresorption in vitro and in vivo has been presented (see V. W. Englemanet al., “A Peptidomimetic Antagonist of the αvβ3 Integrin Inhibits BoneResorption In Vitro and Prevents Osteoporosis In Vivo,” J. Clin. Invest.99: 2284-2292 (1997); S. B. Rodan et al., “A High Affinity Non-Peptideαvβ3 ligand Inhibits Osteoclast Activity In Vitro and In Vivo,” J. BoneMiner. Res. 11: S289 (1996); J. F. Gourvest et al., “Prevention ofOVX-Induced Bone Loss With a Non-peptidic Ligand of the αvβ3 VitronectinReceptor,” Bone 23: S612 (1998); M. W. Lark et al., “An Orally ActiveVitronectin Receptor αvβ3 Antagonist Prevents Bone Resorption In Vitroand In Vivo in the Ovariectomized Rat,” Bone 23: S219 (1998)). Otherαvβ3 antagonists are described in R. M. Keenan et al., “Discovery ofPotent Nonpeptide Vitronectin Receptor (αvβ3) Antagonists,” J. Med.Chem. 40: 2289-2292 (1997); R. M. Keenan et al., “BenzimidazoleDerivatives As Arginine Mimetics in 1,4-Benzodiazepine NonpeptideVitronectin Receptor (αvβ3) Antagonists,” Bioorg. Med. Chem. Lett. 8:3165-3170 (1998); and R. M. Keenan et al., “Discovery of anImidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide VitronectinReceptor (αvβ3) Antagonist With Efficacy in a Restenosis Model,” Bioorg.Med. Chem. Lett. 8: 3171-3176 (1998). Still other benzazepine,benzodiazepine and benzocycloheptene αvβ3 integrin receptor antagonistsare described in the following patent publications: WO 96/00574, WO96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 91/24122, WO97/24124, WO 98/14192, WO 98/15278, WO 99/05107, WO 99/06049, WO99/15170, WO 99/15178, WO 99/15506, and U.S. Pat. No. 6,159,964, and WO97/34865. αvβ3 integrin receptor antagonists having dibenzocycloheptene,dibenzocycloheptane and dibenzoxazepine scaffolds have been described inWO 97/01540, WO 98/30542, WO 99/11626, WO 99/15508, WO 00/33838, U.S.Pat. Nos. 6,008,213, and 6,069,158. Other osteoclast integrin receptorantagonists incorporating backbone conformational ring constraints havebeen described in the patent literature. Published patent applicationsor issued patents disclosing antagonists having a phenyl constraintinclude WO 98/00395, WO 99/32457, WO 99/37621, WO 99/44994, WO 99/45927,WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, EP 0 820,988, EP 0820,991, U.S. Pat. Nos. 5,741,796; 5,773,644; 5,773,646; 5,843,906;5,852,210; 5,929,120; 5,952,381; 6,028,223; and 6,040,311. Publishedpatent applications or issued patents disclosing antagonists having amonocyclic ring constraint include WO 99/26945, WO 99/30709, WO99/30713, WO 99/31099, WO 99/59992, WO 00/00486, WO 00/09503, EP 0796,855, EP 0 928,790, EP 0 928,793, U.S. Pat. Nos. 5,710,159;5,723,480; 5,981,546; 6,017,926; and 6,066,648. Published patentapplications or issued patents disclosing antagonists having a bicyclicring constraint include WO 98/23608, WO 98/35949, WO 99/33798, EP 0853,084, U.S. Pat. Nos. 5,760,028; 5,919,792; and 5,925,655. Referenceis also made to the following reviews for additional scientific andpatent literature that concern alpha v integrin antagonists: M. E.Duggan, et al., “Ligands to the integrin receptor αvβ3, Exp. Opin. Ther.Patents, 10: 1367-1383 (2000); M. Gowen, et al., “Emerging therapies forosteoporosis,” Emerging Drugs, 5: 143 (2000); J. S. Kerr, et al., “Smallmolecule αv integrin antagonists: novel anticancer agents,” Exp. Opin.Invest. Drugs, 9: 1271-1291 (2000); and W. H. Miller, et al.,“Identification and in vivo efficacy of small-molecule antagonists ofintegrin αvβ3 (the vitronectin receptor),” Drug Discovery Today, 5:397-408 (2000).

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.

Members of the class of HMG-CoA reductase inhibitors, known as the“statins,” have been found to trigger the growth of new bone, replacingbone mass lost as a result of osteoporosis (see The Wall Street Journal,Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise forthe treatment of bone resorption. Examples of HMG-CoA reductaseinhibitors include statins in their lactonized or dihydroxy open acidforms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767);simvastatin (see U.S. Pat. No. 4,444,784); dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof;pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227); fluvastatin, particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772); atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995); cerivastatin, particularly the sodiumsalt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin, also known asZD-4522 (see U.S. Pat. No. 5,260,440) and pitavastatin, also referred toas NK-104, itavastatin, or nisvastatin (see PCT internationalapplication publication number WO 97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, may also be employed together with the tissue selectiveandrogen receptor modulators of structural formula I. The proton ATPasewhich is found on the apical membrane of the osteoclast has beenreported to play a significant role in the bone resorption process.Therefore, this proton pump represents an attractive target for thedesign of inhibitors of bone resorption which are potentially useful forthe treatment and prevention of osteoporosis and related metabolicdiseases [see C. Farina et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone antiresorptive agents,” DDT, 4:163-172 (1999)].

The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts [see M. Nakagawa et al.,“Vascular endothelial growth factor (VEGF) directly enhancesosteoclastic bone resorption and survival of mature osteoclasts,” FEBSLetters, 473: 161-164 (2000)]. Therefore, the development of antagonistsof VEGF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1,may provide yet a further approach to the treatment or prevention ofbone resorption.

Activators of the peroxisome proliferator-activated receptor-γ (PPARγ),such as the thiazolidinediones (TZD's), inhibit osteoclast-like cellformation and bone resorption in vitro. Results reported by R. Okazakiet al. in Endocrinology, 140: 5060-5065 (1999) point to a localmechanism on bone marrow cells as well as a systemic one on glucosemetabolism. Nonlimiting examples of PPARγ activators include theglitazones, such as troglitazone, pioglitazone, rosiglitazone, and BRL49653.

Calcitonin may also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. Calcitonin ispreferentially employed as salmon nasal spray (Azra et al., Calcitonin.1996. In: J. P. Bilezikian, et al., Ed., Principles of Bone Biology, SanDiego: Academic Press; and Silverman, “Calcitonin,” Rheumatic DiseaseClinics of North America. 27: 187-196, 2001)

Protein kinase inhibitors may also be employed together with the tissueselective androgen receptor modulators of structural formula I. Kinaseinhibitors include those disclosed in WO 01/17562 and are in oneembodiment selected from inhibitors of p38. Specific embodiments of p38inhibitors useful in the present invention include SB 203580 [Badger etal., “Pharmacological profile of SB 203580, a selective inhibitor ofcytokine suppressive binding protein/p38 kinase, in animal models ofarthritis, bone resorption, endotoxin shock, and immune function,” J.Pharmacol. Exp. Ther., 279: 1453-1461 (1996)].

Osteoanabolic agents are those agents that are known in the art to buildbone by increasing the production of the bone protein matrix. Suchosteoanabolic agents include, for example, the various forms ofparathyroid hormone (PTH) such as naturally occurring PTH (1-84), PTH(1-34), analogs thereof, native or with substitutions and particularlyparathyroid hormone subcutaneous injection. PTH has been found toincrease the activity of osteoblasts, the cells that form bone, therebypromoting the synthesis of new bone (Modern Drug Discovery, Vol. 3, No.8, 2000). In studies reported at the First World Congress onOsteoporosis held in Chicago in June 2000, women in combinedPTH-estrogen therapy exhibited a 12.8% increase in spinal bone mass anda 4.4% increase in total hip mass. Another study presented at the samemeeting showed that PTH could increase bone size as well as density. Aclinical trial of the effect of the human parathyroid hormone 1-34fragment [hPTH(1-34)] on postmenopausal osteoporotic women resulted in≧65% reduction in spine fractures and a 54% reduction in nonvertebralfractures, after a median of 22 months of treatment [see J. M. Hock,Bone, 27: 467-469 (2000) and S. Mohan, et al., Bone, 27: 471-478 (2000),and references cited therein]. Thus, PTH and fragments thereof, such ashPTH(1-34), may prove to be efficacious in the treatment of osteoporosisalone or in combination with other agents, such as the tissue selectiveandrogen receptor modulators of the present invention. An injectablerecombinant form of human PTH, Forteo (teriparatide), has receivedregulatory approval in the U.S. for the treatment of osteoporosis.

Also useful in combination with the SARMs of the present invention arecalcium receptor antagonists which induce the secretion of PTH asdescribed by Gowen et al., in “Antagonizing the parathyroid calciumreceptor stimulates parathyroid hormone secretion and bone formation inosteopenic rats,” J. Clin. Invest. 105:1595-604 (2000).

Growth hormone secretagogues, growth hormone, growth hormone releasinghormone and the like are also osteoanabolic agents which may be employedwith the compounds according to structural formula I for the treatmentof osteoporosis. Representative growth hormone secretagogues aredisclosed in U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat.No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241; U.S.Pat. No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,317,017;U.S. Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat. No.5,434,261; U.S. Pat. No. 5,438,136; U.S. Pat. No. 5,494,919; U.S. Pat.No. 5,494,920; U.S. Pat. No. 5,492,916; U.S. Pat. No. 5,536,716; EPOPatent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT PatentPub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub.No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO95/34311; PCT Patent Pub. No. WO 96/02530; Science, 260, 1640-1643 (Jun.11, 1993); Ann. Rep. Med. Chem., 28: 177-186 (1993); Bioorg. Med. Chem.Lett., 4: 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA, 92:7001-7005 (1995).

Insulin-like growth factor (IGF) may also be employed together with thetissue selective androgen receptor modulators of structural formula I.Insulin-like growth factors may be selected from Insulin-like GrowthFactor I, alone or in combination with IGF binding protein 3 and IGF II[See Johannson and Rosen, “The IGFs as potential therapy for metabolicbone diseases,” 1996, In: Bilezikian, et al., Ed., Principles of BoneBiology, San Diego: Academic Press; and Ghiron et al., “Effects ofrecombinant insulin-like growth factor-I and growth hormone on boneturnover in elderly women,” J. Bone Miner. Res. 10: 1844-1852 (1995)].

Bone morphogenetic protein (BMP) may also be employed together with thetissue selective androgen receptor modulators of structural formula I.Bone morphogenetic protein includes BMP 2, 3, 5, 6, 7, as well asrelated molecules TGF beta and GDF 5 [Rosen et al., “Bone morphogeneticproteins,” 1996. In: J. P. Bilezikian, et al., Ed., Principles of BoneBiology, San Diego: Academic Press; and Wang E A, “Bone morphogeneticproteins (BMPs): therapeutic potential in healing bony defects,” TrendsBiotechnol., 11: 379-383 (1993)].

Inhibitors of BMP antagonism may also be employed together with thetissue selective androgen receptor modulators of structural formula I.BMP antagonist inhibitors are in one embodiment selected from inhibitorsof the BMP antagonists SOST, noggin, chordin, gremlin, and dan [Massagueand Chen, “Controlling TGF-beta signaling,” Genes Dev., 14: 627-644,2000; Aspenberg et al., “The bone morphogenetic proteins antagonistNoggin inhibits membranous ossification,” J. Bone Miner. Res. 16:497-500, 2001; Brunkow et al., “Bone dysplasia sclerosteosis resultsfrom loss of the SOST gene product, a novel cystine knot-containingprotein,” Am. J. Hum. Genet. 68: 577-89 (2001)].

The tissue-selective androgen receptor modulators of the presentinvention may also be combined with the polypeptide osteoprotegerin forthe treatment of conditions associated with bone loss, such asosteoporosis. Preferably osteoprotegerin is mammalian osteoprotegerinand more preferably human osteoprotegerin. The polypeptideosteoprotegerin, a member of the tumor necrosis factor receptorsuperfamily, is useful to treat bone diseases characterized by increasedbone loss, such as osteoporosis. Reference is made to U.S. Pat. No.6,288,032, which is incorporated by reference herein in its entirety.

Prostaglandin derivatives may also be employed together with the tissueselective androgen receptor modulators of structural formula I.Prostaglandin derivatives are in one embodiment selected from agonistsof prostaglandin receptor EP1, EP2, EP4, FP and IP or a derivativethereof [Pilbeam et al., “Prostaglandins and bone metabolism,” 1996. In:Bilezikian, et al. Ed. Principles of Bone Biology, San Diego: AcademicPress; Weinreb et al., “Expression of the prostaglandin E(2) (PGE(2))receptor subtype EP(4) and its regulation by PGE(2) in osteoblastic celllines and adult rat bone tissue,” Bone, 28: 275-281 (2001)].

Fibroblast growth factors may also be employed together with the tissueselective androgen receptor modulators of structural formula I.Fibroblast growth factors include aFGF, bFGF and related peptides withFGF activity [Hurley Florkiewicz, “Fibroblast growth factor and vascularendothelial growth factor families,” 1996. In: J. P. Bilezikian, et al.,Ed. Principles of Bone Biology, San Diego: Academic Press].

In addition to bone resorption inhibitors and osteoanabolic agents,there are also other agents known to be beneficial for the skeletonthrough mechanisms which are not precisely defined. These agents mayalso be favorably combined with the tissue selective androgen receptormodulators of structural formula I.

Vitamin D and vitamin D derivatives may also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin D and vitamin D derivatives include natural vitamin D,25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3, 1α-OH-vitamin D3, 1α-OH-vitaminD2, dihydrotachysterol, 26,27-F6-1α,25(OH)₂ vitamin D3,19-nor-1α,25(OH)₂ vitamin D3, 22-oxacalcitriol, calcipotriol,1α,25(OH)₂-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089,20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71, 1α,24(S)—(OH)₂ vitamin D3,1α,24(R)—(OH)₂ vitamin D3 [See, Jones G., “Pharmacological mechanisms oftherapeutics: vitamin D and analogs,” 1996. In: J. P. Bilezikian, et.al. Ed. Principles of Bone Biology, San Diego: Academic Press].

Vitamin K and vitamin K derivatives may also be employed together withthe tissue selective androgen receptor modulators of structural formulaI. Vitamin K and vitamin K derivatives include menatetrenone (vitaminK2) [see Shiraki et al., “Vitamin K2 (menatetrenone) effectivelyprevents fractures and sustains lumbar bone mineral density inosteoporosis,” J. Bone Miner. Res., 15: 515-521 (2000)].

Soy isoflavones, including ipriflavone, may be employed together withthe tissue selective androgen receptor modulators of structural formulaI.

Fluoride salts, including sodium fluoride (NaF) and monosodiumfluorophosphate (MFP), may also be employed together with the tissueselective androgen receptor modulators of structural formula I. Dietarycalcium supplements may also be employed together with the tissueselective androgen receptor modulators of structural formula I. Dietarycalcium supplements include calcium carbonate, calcium citrate, andnatural calcium salts (Heaney. Calcium. 1996. In: J. P. Bilezikian, etal., Ed., Principles of Bone Biology, San Diego: Academic Press).

Daily dosage ranges for bone resorption inhibitors, osteoanabolic agentsand other agents which may be used to benefit the skeleton when used incombination with a compound of structural formula I are those which areknown in the art. In such combinations, generally the daily dosage rangefor the tissue selective androgen receptor modulator of structuralformula I is 0.01 to 1000 mg per adult human per day, more preferablyfrom 0.1 to 200 mg/day. However, adjustments to decrease the dose ofeach agent may be made due to the increased efficacy of the combinedagent.

In particular, when a bisphosphonate is employed, dosages of 2.5 to 100mg/day (measured as the free bisphosphonic acid) are appropriate fortreatment, more preferably 5 to 20 mg/day, especially about 10 mg/day.Prophylactically, doses of about 2.5 to about 10 mg/day and especiallyabout 5 mg/day should be employed. For reduction in side-effects, it maybe desirable to administer the combination of a compound of structuralformula I and the bisphosphonate once a week. For once weeklyadministration, doses of about 15 mg to 700 mg per week ofbisphosphonate and 0.07 to 7000 mg of a compound of structural formula Imay be employed, either separately, or in a combined dosage form. Acompound of structural formula I may be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

For the treatment of atherosclerosis, hypercholesterolemia, andhyperlipidemia, the compounds of structural formula I may be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be lipid-altering compoundssuch as HMG-CoA reductase inhibitors, or agents having otherpharmaceutical activities, or agents that have both lipid-alteringeffects and other pharmaceutical activities. Examples of HMG-CoAreductase inhibitors include statins in their lactonized or dihydroxyopen acid forms and pharmaceutically acceptable salts and estersthereof, including but not limited to lovastatin (see U.S. Pat. No.4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin, particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatin,also referred to as NK-104 (see PCT international applicationpublication number WO 97/23200). Additional active agents which may beemployed in combination with a compound of structural formula I include,but are not limited to, HMG-CoA synthase inhibitors; squalene epoxidaseinhibitors; squalene synthetase inhibitors (also known as squalenesynthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase(ACAT) inhibitors including selective inhibitors of ACAT-1 or ACAT-2 aswell as dual inhibitors of ACAT-1 and -2; microsomal triglyceridetransfer protein (MTP) inhibitors; probucol; niacin; cholesterolabsorption inhibitors, such as SCH-58235, also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPARγ) agonists, including the compoundscommonly referred to as glitazones, for example troglitazone,pioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidinediones as well as thosePPARγ agonists outside the thiazolidinedione structural class; PPARαagonists, such as clofibrate, fenofibrate including micronizedfenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (alsoknown as pyridoxine) and the pharmaceutically acceptable salts thereofsuch as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folicacid or a pharmaceutically acceptable salt or ester thereof such as thesodium salt and the methylglucamine salt; anti-oxidant vitamins such asvitamin C and E and beta carotene; beta-blockers; angiotensin IIantagonists such as losartan; angiotensin converting enzyme inhibitors,such as enalapril and captopril; calcium channel blockers, such asnifedipine and diltiazem; endothelin antagonists; agents such as LXRligands that enhance ABC1 gene expression; bisphosphonate compounds,such as alendronate sodium; and cyclooxygenase-2 inhibitors, such asrofecoxib and celecoxib, as well as other agents known to be useful inthe treatment of these conditions.

Daily dosage ranges for HMG-CoA reductase inhibitors when used incombination with the compounds of structural formula I correspond tothose which are known in the art. Similarly, daily dosage ranges for theHMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; cholesterol absorption inhibitorsincluding ezetimibe; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors,including glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists; PPARα agonists; PPAR dual α/γ agonists; vitamin B₆; vitaminB₁₂; folic acid; anti-oxidant vitamins; beta-blockers; angiotensin IIantagonists; angiotensin converting enzyme inhibitors; calcium channelblockers; endothelin antagonists; agents such as LXR ligands thatenhance ABC1 gene expression; bisphosphonate compounds; andcyclooxygenase-2 inhibitors also correspond to those which are known inthe art, although due to the combined action with the compounds ofstructural formula I, the dosage may be somewhat lower when administeredin combination.

One embodiment of the invention is a method for effecting a boneturnover marker in a mammal comprising administering a therapeuticallyeffective amount of a compound according to formula I. Non-limitingexamples of bone turnover markers can be selected from urinaryC-telopeptide degradation products of type I collagen (CTX), urinaryN-telopeptide cross-links of type I collagen (NTX), DXA, and DPD.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term “administering” is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating diseases caused byandrogen deficiency or that can be ameliorated by addition of androgen.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention

-   -   AcOH Acetic acid    -   BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   Bu Butyl    -   calc. Calculated    -   CH₂Cl₂ Methylene chloride    -   CBZ (Cbz) Benzyloxycarbonyl    -   Cs₂CO₃ Cesium carbonate    -   DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone    -   DEAD Diethyl azodicarboxylate    -   DIBAL Diisobutylaluminum hydride    -   DIEA Diisopropylethylamine    -   DMAP 4-Dimethylaminopyridine    -   DMF N,N-Dimethylformamide    -   DMSO Dimethyl sulfoxide    -   EDC 1-(3-Dimethylaminopropyl)3-ethylcarbodiimide HCl    -   ES-MS Electron-spray mass spectroscopy    -   Et ethyl    -   Et₂O Diethyl ether    -   Et₃N Triethylamine    -   EtOAc Ethyl acetate    -   FAB Fast atom bombardment    -   FN(SO₂Ph)₂ N-Fluorobenzenesulfonimide    -   HOAt 1-Hydroxy-7-azabenzotriazole    -   HOBt N-hydroxybenzotriazole    -   HPLC High-performance liquid chromatography    -   HRMS High resolution mass spectrum    -   i-PrOH Isopropyl alcohol    -   LAH Lithium aluminum hydride    -   LDA Lithium diisopropylamide    -   Me Methyl    -   MF molecular formula    -   MgSO₄ Magnesium sulfate    -   MS mass spectrum    -   NMM N-methylmorpholine    -   Na₂SO₄ Sodium sulfate    -   Ph Phenyl    -   PhS(O)OMe Methyl benzenesulfinate    -   Pr Propyl    -   r.t. Room temperature    -   NaHCO₃ Sodium hydrogencarbonate    -   TFA Trifluoroacetic acid    -   THF Tetrahydrofuran    -   TLC Thin-layer chromatography.        Preparation of the Compounds of the Invention

The compounds of the present invention can be prepared according to theprocedures denoted in the following reaction Schemes and Examples ormodifications thereof using readily available starting materials,reagents, and conventional procedures or variations thereof well-knownto a practitioner of ordinary skill in the art of synthetic organicchemistry. Specific definitions of variables in the Schemes are givenfor illustrative purposes only and are not intended to limit theprocedures described.

The selective androgen receptor modulators (SARMs) of structural formula1-5 were prepared as outlined in Scheme 1. The starting material was the17β-carboxylate 1-1 which is disclosed in G. H. Rasmusson et al., J.Med. Chem., 27: 1690-1701 (1984).

Alternatively the compounds of structural formula 1-5 were prepared fromintermediate 1-3 as shown in Scheme 2:

Compounds of structural formula 3-6 in Scheme 3 were prepared asoutlined in Scheme 3 below. The starting material was the 17β-carboxylicacid 3-1 which is disclosed in G. H. Rasmusson et al., J. Med. Chem.,29: 2298-2315 (1986) and R. L. Tolman, et al., J. Steroid Biochem. Mol.Biol., 60: 303-309 (1997).

Alternatively the compounds of structural formula 3-6 were prepared fromintermediate 3-5 as shown in Scheme 4:

The following examples are provided to further illustrate details forthe preparation and use of the compounds of the present invention. Theyare not intended to be limitations on the scope of the instant inventionin any way, and they should not be so construed. Furthermore, thecompounds described in the following examples are not to be construed asforming the only genus that is considered as the invention, and anycombination of the compounds or their moieties may itself form a genus.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are in degreesCelsius unless noted otherwise.

EXAMPLE 1 Step A:2α-Fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxylic acid methylester (1-2)

To a solution of 1-1 (7.5 g, 21.6 mmol) in THF (100 mL) at −78° C. wasadded a solution of 1.5 M LDA in THF (17.3 mL, 25.9 mmol) dropwise over20 min and then stirred 1 h. A solution of FN(SO₂Ph)₂ (10.2 g, 32.4mmol) in THF (40 mL) was then added over 20 min. After 30 min, thecooling bath was removed and the reaction was stirred for 14 h. Et₂O wasadded, and the mixture was washed with water, saturated aqueous sodiumhydrogencarbonate, brine, dried (MgSO₄) and then concentrated.Chromatography on silica gel (hexanes to EtOAc as eluent) gave 1-2 (4.2g) as a colorless solid.

MS calculated M+H: 366. found 366.1.

Step B: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylicacid methyl ester (1-3)

To a solution of 1-2 (30 g, 82.1 mmol) in THF (400 mL) at −78° C. wasadded a solution of 1.5 M LDA in THF (71.1 mL, 107 mmol) dropwise over30 min and then stirred 1 h. Methyl benzenesulfinate (19.23 g, 123 mmol)was then added over 15 min. After 30 min, the cooling bath was removedand the reaction was stirred for 1 h. Et₂O was added, and the mixturewas washed with water, saturated aqueous sodium hydrogencarbonate,brine, dried (MgSO₄) and then concentrated. The residue was dissolved intoluene (200 mL) and heated at reflux for 2 h. Solvent evaporation andchromatography of the residue on silica gel (hexanes to 50%EtOAc/hexanes as eluent) gave 1-3 (20.4 g) as a pale yellow solid.

MS calculated M+H: 364. found 364.1.

Step C: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylicacid (1-4)

To a solution of 1-3 (2.4 g, 6.6 mmol) in 1,4-dioxane (50 mL) was addeda solution of lithium hydroxide (0.41 g, 9.9 mmol) in water (20 mL), andthe mixture heated at 100° C. for 3 h. After cooling, the mixture wasdiluted with ethyl acetate and then washed with 1N HCl, brine, dried(MgSO₄) and then concentrated to give 1-4 (2.2 g) as a pale yellowsolid.

MS calculated M+H: 350. found 350.

Step D:N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide(5-1)

A mixture of 1-4 (0.12 g, 0.34 mmol), EDC (0.079 g, 0.41 mmol), HOAt(0.056 g, 0.41 mmol), NMM (0.15 mL, 1.37 mmol) and 2-fluorobenzylamine(0.52 g, 0.41 mmol) in DMF (2 mL) stirred for 14 h. The mixture wasdiluted with water, filtered, and the solids washed with water, thendiethyl ether, and then dried under vacuum to give 5-1 (0.12 g) as apale yellow solid.

MS calculated M+H, 457.2661 found 457.2666.

EXAMPLE 2 Step A:S-(Pyridin-2-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carbothioate(2-1)

A mixture of 1-4 (0.80 g, 2.30 mmol), 2,2′-dithiopyridine (1.01 g, 4.6mmol) and triphenylphosphine (1.2 g, 4.6 mmol) in toluene (10 mL) wasstirred 14 h. Following evaporation of the solvent, the solids weresuspended in toluene (5 mL) and diluted with diethyl ether. The solidswere collected by filtration, washed with diethyl ether, and then driedunder vacuum to give 2-1 (0.12 g) as a pale yellow solid.

MS calculated M+H: 443. found 443.

Step B:N-(2-Trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide(6-1)

A mixture of 2-1 (0.25 g, 0.57 mmol), 2-trifluoromethylaniline (0.18 g,1.13 mmol) and silver(II) triflate (0.15 g, 0.57 mmol) indichloromethane (3 mL) was stirred 14 h. Following evaporation of thesolvent, chromatography of the residue on silica gel (hexanes to EtOAcas eluent) gave 6-1 (0.12 g) as a pale yellow solid.

MS calculated M+H, 493.2473. found 493.2470.

Examples 3-50 in Table 1 were prepared in a similar manner as Examples 1and 2, but using the appropriate amine to generate the carboxamide.

TABLE 1

Mass spectrum Ex. NR²R³ Measured [M + H] 3

457.2663 4

459.2205 5

440.2747 6

4572645 7

429.2536 8

445.2302 9

507.2637 10

479.2829 11

493.2966 12

493.2175 13

5612873 14

5132450 15

509.2947 16

496.2410 17

497.2825 18

446.2278 19

465.2910 20

465.2911 21

460.2436 22

446.2274 23

446.2274 24

429.2555 25

445.2319 26

443.2815 27

455.2826 28

443.2809 29

430.2509 30

431.2325 31

527.2061 32

455.2714 33

439.2750 34

439.2750 35

439.2754 36

425.2611 37

443.2503 38

443.2505 39

443.2504 40

477.2114 41

461.2420 42

453.2920 43

453.2920 44

447.3032 45

447.3043 46

497.2813 47

497.2795 48

49

433.2849 50

480.2763

EXAMPLE 51 Step A: 4-Methyl-3-oxo-4-aza-5α-androstane-17β-carboxylicacid (3-2)

To a suspension of 3-1 (13.2 g, 39.82 mmol) and EtOH (200 ml) was addedLiOH (2 g, 47.8 mmol, dissolved in 20 ml H₂O). To the solution was added10% Pd/C (1 g) and then the mixture was stirred under 1 atm H₂ for 4.0hours. The reaction was filtered through a celite pad and thenconcentrated. To the residue was added 1N HCl. The solid that formed wascollected, washed with Et₂O and then dried under vacuum to give 3-2(10.5 g) as a white solid.

Step B: 4-Methyl-3-oxo-4-aza-5α-androstane-17β-carboxylic acid4-methoxybenzyl ester (3-3)

To a suspension of 3-2 (10.5 g, 31.48 mmol) and DMF (200 ml) was addedCs₂CO₃ (10 g, 47.8 mmol) and 4-methoxybenzyl chloride (5.9 g, 37.78mmol). The mixture was heated to 60° C. overnight. EtOAc was added, andthe mixture was washed with 1N HCl, brine, dried (MgSO₄) andconcentrated. The residue was trituated with EtOAc and then filtered.The solution was concentrated and the residue subjected tochromatography on silica gel (hexanes to EtOAc as eluent) to give 3-3(7.22 g) as a white solid.

MS calculated M+H, 454.6. found 454.3.

Step C: 2α-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylicacid 4-methoxybenzyl ester (3-4)

To a solution of 3-3 (7.2 g, 15.9 mmol) in THF (100 mL) at −78° C. wasadded a solution of 1.5 M LDA in THF (12.7 mL, 19.05 mmol) dropwise over20 min and then stirred for 1 h. A solution of FN(SO₂Ph)₂ (6.0 g, 19.05mmol) in THF (40 mL) was then added over 20 min. After 30 min, thecooling bath was removed and the reaction was stirred for 14 h. Et₂O wasadded and then washed with water, saturated aqueous sodiumhydrogencarbonate, brine, dried (MgSO₄) and then concentrated.Chromatography on silica gel (hexanes to EtOAc as eluent) gave 3-4 (3.1g) as a colorless solid.

MS calculated M+H, 472.6. found 472.3.

Step D: 2α-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylicacid (3-5)

To a solution of 3-4 (3.1 g, 6.57 mmol) in CH₂Cl₂ (20 ml) was added TFA(10 ml). After 30 minutes, the solution was concentrated and thenazeotroped with toluene. The residue was dissolved in CH₂Cl₂ and thenwashed with 1N HCl, brine, dried (MgSO₄) and then concentrated to give3-5 (2.1 g) as white solid.

MS calculated M+H, 352.5. found 352.2.

Step E:N-(2-Fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide(7-1)

A mixture of 3-5 (0.10 g, 0.285 mmol), EDC (0.066 g, 0.34 mmol), HOAt(0.047 g, 0.34 mmol), NMM (0.13 mL, 1.14 mmol) and 2-fluorobenzylamine(0.52 g, 0.41 mmol) in DMF (2 mL) stirred for 14 h. The mixture wasdiluted with water, filtered, and the solids washed with water, thendiethyl ether, and then dried under vacuum to give 7-1 (0.12 g) as apale yellow solid.

MS calculated M+H, 459.2818 found 459.2812.

EXAMPLE 52 Step A:S-(Pyridin-2-yl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carbothioate(4-1)

Utilizing the procedure described in Scheme 4, 4-1 was prepared from3-5. MS calculated M+H: 445. found 445.1.

Step B:N-(2-Trifluorophenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide(8-1)

Utilizing the procedure described in Scheme 4, 8-1 was prepared from4-1. MS found M+H, 495.2624.

Examples 53-67 in Table 2 were prepared in a similar manner as Examples51 and 52, but using the appropriate amine to generate the carboxamide.

TABLE 2

Mass spectrum Ex. NR³R⁴ Measured [M + H] 53

459.2811 54

459.2807 55

481.2970 56

495.3122 57

433.2478 58

448.2433 59

431.2715 60

447.2479 61

509.2786 62

457.2874 63

457.2873 64

461.2374 65

386.957  66

455.3082 67

455.3078

EXAMPLE 68 Oral Composition

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of a compound of the present invention is formattedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size 0 hard gelatin capsule.

EXAMPLE 69

Transdermal Patch Formulation Ingredient Amount Compound of formula I 40g Silicone fluid 45 g Colloidal silicone dioxide 2.5 g The silicone fluid and compound of structural formula I are mixedtogether and the colloidal silicone dioxide is added to increaseviscosity. The material is then dosed into a subsequently heat sealedpolymeric laminate comprised of the following: polyester release liner,skin contact adhesive composed of silicone or acrylic polymers, acontrol membrane which is a polyolefin (e.g. polyethylene, polyvinylacetate or polyurethane), and an impermeable backing membrane made of apolyester multilaminate. The resulting laminated sheet is then cut into10 cm² patches. For 100 Patches.

EXAMPLE 70

Suppository Ingredient Amount Compound of structural formula I  25 gPolyethylene glycol 1000 1481 g Polyethylene glycol 4000  494 gThe polyethylene glycol 1000 and polyethylene glycol 4000 are mixed andmelted. The compound of structural formula I is mixed into the moltenmixture, poured into molds and allowed to cool. For 1000 suppositories.

EXAMPLE 71

Injectable solution Ingredient Amount Compound of structural formula I 5 g Buffering agents q.s. Propylene glycol 400 mg Water for injection600 mLThe compound of structural formula I and buffering agents are dissolvedin the propylene glycol at about 50° C. The water for injection is thenadded with stirring and the resulting solution is filtered, filled intoampules, sealed and sterilized by autoclaving. For 1000 Ampules.

EXAMPLE 72

Injectable solution Ingredient Amount Compound of structural formula I 5 g Buffering agents q.s. Magnesium sulfate heptahydrate 100 mg Waterfor injection 880 mLThe compound of structural formula I, magnesium sulfate heptahydrate andbuffering agents are dissolved in the water for injection with stirring,and the resulting solution is filtered, filled into ampoules, sealed andsterilized by autoclaving. For 1000 Ampoules.

The following assays were used to characterize the activity of thetissue selective androgen receptor modulators of the present invention.

In Vitro and In Vivo Assays for Identification of Compounds with SARMActivity

1. Hydroxylapatite-Based Radioligand Displacement Assay of CompoundAffinity for Endogenously Expressed AR Materials:

Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mMbeta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)

50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM Tris, pH8.0 and 1 mM EDTA.

Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA. 95%EtOH

Methyltrienolone, [17α-methyl-³H], (R1881*); NEN NET590

Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)

Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453

Hydroxylapatite Fast Flow; Calbiochem Cat#391947

Molybdate=Molybdic Acid (Sigma, M1651)

MDA-MB-453 cell culture media:

RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO₃, 2 mM L-glutamine In 500 mLof complete media Final conc. 10 mL (1M Hepes) 20 mM 5 mL (200 mM L-glu) 4 mM 0.5 mL (10 mg/mL human insulin) 10 μg/mL in 0.01 N HClCalbiochem#407694-S) 50 mL FBS (Sigma F2442) 10% 1 mL (10 mg/mLGentamicin 20 μg/mL Gibco#15710-072)Cell Passaging:

Cells (Hall R. E., et al., European Journal of Cancer, 30A: 484-490(1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA is dilutedin the same PBS 1:10. The cell layers are rinsed with 1× Trypsin, extraTrypsin is poured out, and the cell layers are incubated at 37° C. for˜2 min. The flask is tapped and checked for signs of cell detachment.Once the cells begin to slide off the flask, the complete media is addedto kill the trypsin. The cells are counted at this point, then dilutedto the appropriate concentration and split into flasks or dishes forfurther culturing (Usually 1:3 to 1:6 dilution).

Preparation of MDA-MB-453 Cell Lysate

When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 min at4° C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mMEDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate,pH 7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid nitrogen or ethanol/dry ice bath and transferred to −80° C.freezer on dry ice. Before setting up the binding assay, the frozensamples are left on ice-water to just thaw (˜1 hr). Then the samples arecentrifuged at 12,500 g to 20,000 g for 30 min at 4° C. The supernatantis used to set-up assay right away. If using 50 μL of supernatant, thetest compound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening:

1×TEGM buffer is prepared, and the isotope-containing assay mixture isprepared in the following order: EtOH (2% final concentration inreaction), ³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and1×TEGM. [eg. For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10³H-R1881 stock+2300 μL (100×23) 1×TEGM]. The compound is seriallydiluted, e.g., if starting final conc. is 1 μM, and the compound is in25 μL of solution, for duplicate samples, 75 μL of 4×1 μM solution ismade and 3 μL of 100 μM is added to 72 μL of buffer, and 1:5 serialdilution.

25 μL of ³H-R1881 trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight. 100 μL of 50% HAP slurry is prepared and added to theincubated reaction which is then vortexed and incubated on ice for 5 to10 minutes. The reaction mixture is vortexed twice more to resuspend HAPwhile incubating reaction. The samples in 96-well format are then washedin wash buffer using The FilterMate™ Universal Harvester plate washer(Packard). The washing process transfers HAP pellet containingligand-bound expressed receptor to Unifilter-96 GF/B filter plate(Packard). The HAP pellet on the filter plate is incubated with 50 μL ofMICROSCINT (Packard) scintillint for 30 minutes before being counted onthe TopCount microscintillation counter (Packard). IC₅₀s are calculatedusing R1881 as a reference. Tissue selective androgen receptormodulators of the present invention displayed IC₅₀ values of 1micromolar or less.

2. MMP1 Promoter Suppression, Transient Transfection Assay (TRAMPS).

HepG2 cells are cultured in phenol red free MEM containing 10%charcoal-treated FCS at 37 C with 5% CO₂. For transfection, cells areplated at 10,000 cells/well in 96 well white, clear bottom plates.Twenty four hours later, cells are co-transfected with a MMP1promoter-luciferase reporter construct and a rhesus monkey expressionconstruct (50:1 ratio) using FuGENE6 transfection reagent, following theprotocol recommended by manufacturer. The MMP1 promoter-luciferasereporter construct is generated by insertion of a human MMP1 promoterfragment (−179/+63) into pGL2 luciferase reporter construct (Promega)and a rhesus monkey AR expression construct is generated in a CMV-Tag2Bexpression vector (Stratagene). Cells are further cultured for 24 hoursand then treated with test compounds in the presence of 100 nMphorbol-12-myristate-13-acetate (PMA), used to increase the basalactivity of MMP1 promoter. The compounds are added at this point, at arange of 1000 nM to 0.03 nM, 10 dilutions, at a concentration on 10×,1/10th volume (example: 10 microliters of ligand at 10× added to 100microliters of media already in the well). Cells are further culturedfor an additional 48 hours. Cells are then washed twice with PBS andlysed by adding 70 μL of Lysis Buffer (1×, Promega) to the wells. Theluciferase activity is measured in a 96-well format using a 1450Microbeta Jet (Perkin Elmer) luminometer. Activity of test compounds ispresented as suppression of luciferase signal from the PMA-stimulatedcontrol levels. EC₅₀ and Emax values are reported. Tissue selectiveandrogen receptor modulators of the present invention activaterepression typically with submicromolar EC₅₀ values and Emax valuesgreater than about 50%.

REFERENCES

-   a. Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A,    “Fibroblast growth factor receptor signaling activates the human    interstitial collagenase promoter via the bipartite Ets-AP1    element,” Mol. Endocrinol. 11: 1129-44 (1997).-   b. Schneikert J, Peterziel H, Defossez P A, Klocker H, Launoit Y,    Cato A C, “Androgen receptor-Ets protein interaction is a novel    mechanism for steroid hormone-mediated down-modulation of matrix    metalloproteinase expression,” J. Biol. Chem. 271: 23907-23913    (1996).    3. A Mammalian Two-Hybrid Assay for the Ligand-Induced Interaction    of N-Terminus and C-Terminus Domains of the Androgen Receptor    (Agonist Mode)

This assay assesses the ability of AR agonists to induce the interactionbetween the N-terminal domain (NTD) and C-terminal domain (CTD) of rhARthat reflects the in vivo virilizing potential mediated by activatedandrogen receptors. The interaction of NTD and CTD of rhAR is quantifiedas ligand induced association between a Gal4 DBD-rhARCTD fusion proteinand a VP16-rhARNTD fusion protein as a mammalian two-hybrid assay inCV-1 monkey kidney cells.

The day before transfection, CV-1 cells are trypsinized and counted, andthen plated at 20,000 cells/well in 96-well plates or larger plates(scaled up accordingly) in DMEM+10% FCS. The next morning, CV-1 cellsare cotransfected with pCBB1 (Gal4 DBD-rhARLBD fusion constructexpressed under the SV40 early promoter), pCBB2 (VP16-rhAR NTD fusionconstruct expressed under the SV40 early promoter) and pFR (Gal4responsive luciferase reporter, Promega) using LIPOFECTAMINE PLUSreagent (GIBCO-BRL) following the procedure recommended by the vendor.Briefly, DNA admixture of 0.05 μg pCBB1, 0.05 μg pCBB2 and 0.1 μg of pFRis mixed in 3.4 μL OPTI-MEM (GIBCO-BRL) mixed with “PLUS Reagent” (1.6μL, GIBCO-BRL) and incubated at room temperature (RT) for 15 min to formthe pre-complexed DNA.

For each well, 0.4 μL LIPOFECTAMINE Reagent (GIBCO-BRL) is diluted into4.6 μL OPTI-MEM in a second tube and mixed to form the dilutedLIPOFECTAMINE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15min at RT. The medium on the cells is replaced with 40 μL/well OPTI-MEM,and 10 μL DNA-lipid complexes are added to each well. The complexes aremixed into the medium gently and incubated at 37° C. at 5% CO₂ for 5 h.Following incubation, 200 μL/well D-MEM and 13% charcoal-stripped FCSare added, followed by incubation at 37° C. at 5% CO₂. After 24 hours,the test compounds are added at the desired concentration(s) (1 nM-10μM). Forty eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the manufacturer's protocol. Theassay is conducted directly in the wells by sequential addition of 50 μLeach of assay solution 1 followed by assay solution 2. After incubationfor 40 minutes at room temperature, luminescence is directly measuredwith 2-5 second integration.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 3 nM R1881. Typical tissue-selective androgenreceptor modulators of the present invention display weak or no agonistactivity in this assay with less than 50% agonist activity at 10micromolar.

REFERENCES

-   He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M,    “Activation function in the human androgen receptor ligand binding    domain mediates inter-domain communication with the NH(2)-terminal    domain,” J. Biol. Chem. 274: 37219-37225 (1999).    4. A Mammalian Two-Hybrid Assay For Inhibition of Interaction    Between N-Terminus and C-Terminus Domains of Androgen Receptor    (Antagonist Mode)

This assay assesses the ability of test compounds to antagonize thestimulatory effects of R1881 on the interaction between NTD and CTD ofrhAR in a mammalian two-hybrid assay in CV-1 cells as described above.

Forty eight hours after transfection, CV-1 cells are treated with testcompounds, typically at 10 μM, 3.3 μM, 1 μM, 0.33 μM, 100 nM, 33 nM, 10nM, 3.3 nM and 1 nM final concentrations. After incubation at 37° C. at5% CO₂ for 10-30 minutes, an AR agonist methyltrienolone (R1881) isadded to a final concentration of 0.3 nM and incubated at 37° C.Forty-eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the protocol recommended by themanufacturer. The ability of test compounds to antagonize the action ofR1881 is calculated as the relative luminescence compared to the valuewith 0.3 nM R1881 alone.

SARM compounds of the present invention typically displayed antagonistactivity in the present assay with IC₅₀ values less than 1 micromolar.

5. Trans-Activation Modulation of Androgen Receptor (TAMAR)

This assay assesses the ability of test compounds to controltranscription from the MMTV-LUC reporter gene in MDA-MB-453 cells, ahuman breast cancer cell line that naturally expresses the human AR. Theassay measures induction of a modified MMTV LTR/promoter linked to theLUC reporter gene.

20,000 to 30,000 cells/well are plated in a white, clear-bottom 96-wellplate in “Exponential Growth Medium” which consists of phenol red-freeRPMI 1640 containing 10% FBS, 4 mM L-glutamine, 20 mM HEPES, 10 ug/mLhuman insulin, and 20 ug/mL gentamicin. Incubator conditions are 37° C.and 5% CO₂. The transfection is done in batch mode. The cells aretrypsinized and counted to the right cell number in the proper amount offresh media, and then gently mixed with the Fugene/DNA cocktail mix andplated onto the 96-well plate. All the wells receive 200 Tl ofmedium+lipid/DNA complex and are then incubated at 37° C. overnight. Thetransfection cocktail consists of serum-free Optimem, Fugene6 reagentand DNA. The manufacturer's (Roche Biochemical) protocol for cocktailsetup is followed. The lipid (Tl) to DNA (Tg) ratio is approximately 3:2and the incubation time is 20 min at room temperature. Sixteen to 24 hrsafter transfection, the cells are treated with test compounds such thatthe final DMSO (vehicle) concentration is <3%. The cells are exposed tothe test compounds for 48 hrs. After 48 hrs, the cells are lysed by aPromega cell culture lysis buffer for 30-60 min and then the luciferaseactivity in the extracts is assayed in the 96-well format luminometer.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 100 nM R1881.

REFERENCES

-   a. R. E. Hall, et al., “MDA-MB-453, an androgen-responsive human    breast carcinoma cell line with high androgen receptor expression,”    Eur. J. Cancer, 30A: 484-490 (1994).-   b. R. E. Hall, et al., “Regulation of androgen receptor gene    expression by steroids and retinoic acid in human breast-cancer    cells,” Int. J. Cancer., 52: 778-784 (1992).    6. In Vivo Prostate Assay

Male Sprague-Dawley rats aged 9-10 weeks, the earliest age of sexualmaturity, are used in prevention mode. The goal is to measure the degreeto which androgen-like compounds delay the rapid deterioration (˜−85%)of the ventral prostate gland and seminal vesicles that occurs during aseven day period after removal of the testes (orchiectomy [ORX]).

Rats are orchiectomized (ORX). Each rat is weighed, then anesthetized byisoflurane gas that is maintained to effect. A 1.5 cm anteroposteriorincision is made in the scrotum. The right testicle is exteriorized. Thespermatic artery and vas deferens are ligated with 4.0 silk 0.5 cmproximal to the testicle. The testicle is freed by one cut of a smallsurgical scissors distal to the ligation site. The tissue stump isreturned to the scrotum. The same is repeated for the left testicle.When both stumps are returned to the scrotum, the scrotum and overlyingskin are sutured closed with 4.0 silk. For Sham-ORX, all proceduresexcepting ligation and scissors cutting are completed. The rats fullyrecover consciousness and full mobility within 10-15 minutes.

A dose of test compound is administered subcutaneously or orally to therat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

Necropsy and Endpoints:

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 ml whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofORX. Next, the ventral portion of the prostate gland is located andblunt dissected free in a highly stylized fashion. The ventral prostateis blotted dry for 3-5 seconds and then weighed (VPW). Finally, theseminal vesicle is located and dissected free. The ventral seminalvesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate andseminal vesicle. Secondary data include serum LH (luteinizing hormone)and FSH (follicle stimulating hormone), and possible serum markers ofbone formation and virilization. Data are analyzed by ANOVA plus FisherPLSD post-hoc test to identify intergroup differences. The extent towhich test compounds inhibit ORX-induced loss of VPW and SVWT isassessed.

7. In Vivo Bone Formation Assay:

Female Sprague-Dawley rats aged 7-10 months are used in treatment modeto simulate adult human females. The rats have been ovariectomized (OVX)75-180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028 mpk SC, 2×/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15-31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-like compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

In a typical assay, nine groups of seven rats each are studied.

On Days 19 and 29 (fifth and fifteenth days of treatment), a singlesubcutaneous injection of calcein (8 mg/kg) is given to each rat.

Necropsy and Endpoints:

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 mL whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofOVX. First, the uterus is located, blunt dissected free in a highlystylized fashion, blotted dry for 3-5 seconds and then weighed (UW). Theuterus is placed in 10% neutral-buffered formalin. Next, the right legis disarticulated at the hip. The femur and tibia are separated at theknee, substantially defleshed, and then placed in 70% ethanol.

A 1-cm segment of the central right femur, with the femoralproximal-distal midpoint at center, is placed in a scintillation vialand dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10%dibutyl phthalate, that is allowed to polymerize over a 48-72 hr period.The bottle is cracked and the plastic block is trimmed into a shape thatconveniently fits the vice-like specimen holder of a Leica 1600 SawMicrotome, with the long axis of the bone prepared for cross-sectioning.Three cross-sections of 85 μm thickness are prepared and mounted onglass slides. One section from each rat that approximates the midpointof the bone is selected and blind-coded. The periosteal surface of eachsection is assessed for total periosteal surface, single fluorochromelabel, double fluorochrome label, and interlabel distance.

Primary data for this assay are the percentage of periosteal surfacebearing double label and the mineral apposition rate (interlabeldistance(μm)/10d), semi-independent markers of bone formation. Secondarydata include uterus weight and histologic features. Tertiary endpointsmay include serum markers of bone formation and virilization. Data areanalyzed by ANOVA plus Fisher PLSD post-hoc test to identify intergroupdifferences. The extent to which test compounds increase bone formationendpoint are assessed.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, it isunderstood that the practice of the invention encompasses all of theusual variations, adoptions, or modifications, as being within the scopeof the following claims and their equivalents.

1. A method of treating a condition in a mammal selected from weakenedmuscle tone, osteoporosis, osteopenia, glucocorticoid-inducedosteoporosis, comprising administering to the mammal in need of suchtreatment, a therapeutically effective amount of a compound which isN-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide,or a pharmaceutically acceptable salt or enantiomer thereof.
 2. Themethod of claim 1 wherein the compound is:N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide.3. The method of claim 1 wherein the compound is:

pharmaceutically acceptable salts and enantiomers thereof.
 4. The methodof claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 4wherein the condition is weakened muscle tone.
 6. The method of claim 4wherein the condition is sarcopenia.
 7. The method of claim 4 whereinthe condition osteoporosis or osteopenia.